1. Introduction

2. The Role of Hypoxia in HCC

3. TACE of HCC

4. TAE-induced Hypoxia and Its Implications for Tumor Biological Processes

5. Hypoxia-Targeted Therapy for HCC

6. Combination of Hypoxia-Targeted Therapy and TACE for HCC

6.1. Combination of HIF-Related Pathway Inhibitors and TACE

6.1.1. HIF-1

Melatonin is an endogenous hormone secreted by the pineal gland [106]. The anti-tumor mechanism of melatonin is primarily to inhibit tumor angiogenesis by inhibiting the HIF-1α/VEGF signaling pathway [107,108], and also to inhibit tumor metastasis by targeting MMP-2 and MMP-9 to reduce the permeability of the vessel wall [109,110]. As early as 2002, TACE in combination with melatonin (MLT) was used to treat patients with advanced primary HCC [111]. The results demonstrated that MLT reduced hepatic impairment following TACE and enhanced immune activity of patients. Recently, melatonin was loaded on a temperature-sensitive nano gel, p(N-isopropyl-acrylamide-co-butyl methylacrylate) (PIB-M), for tumor embolism in VX2 rabbit models by Chen et al.[112]. The results of the study confirm that melatonin can inhibit the growth and migration of HepG2 and LM3 cells by targeting HIF-1α, MMP-2, MMP-9, and E-cadherin in vitro. Furthermore, the concentration of melatonin in the tumor after embolization remains at a high level for the following three days, which suggests that this sustained effect on the tumor cells and TME may be achieved.

A number of natural compounds have been demonstrated to inhibit HIF-1α and VEGF. The combination with TACE has been shown to have promising evidence of targeting hypoxia, indicating potential for clinical translation in the treatment of hepatocellular carcinoma. 10-Hydroxycamptothecin (HCPT), a camptothecin analog, is a naturally occurring alkaloid with antitumor activity. Camptothecin analogs can mediate S-phase cytotoxic effects, through the induction of a stable DNA-Topo I complex which can lead to DNA linkage breaks. The ability to inhibit HIF-1 has also been found. Our preliminary research [113] found that the levels of HIF-1, VEGF, and microvessel density were comparable following intrahepatic arterial infusion of distilled water and HCPT+TACE (P > .05), indicating that HCPT significantly inhibits the expression of HIF-1 and angiogenesis in postembolization hepatic tumors. This finding suggests that HCPT may have a broader application in this clinical setting. Curcumin is a highly polyphenolic molecule that has been reported to inhibit the viability of cancer cells and is commonly used to prevent or treat a variety of diseases. Dai et al. [114] observed that the levels of tumor HIF-1α, VEGF, and MVD were significantly reduced in the liposomal curcumin combined with TAE in their initial study. Further investigations [115] revealed that, in addition to the aforementioned findings, curcumin liposome was capable of inhibiting survivin levels, and significantly inhibited cell viability and promoted apoptosis in the G1 phase by regulating apoptosis-related molecules. The ginsenoside Rg3 was found to inhibit the nuclear localization of HIF-1α by binding to HIF-1α [116]. Ginsenoside Rg3 in combination with TAE has been shown to significantly decrease CD31, VEGF expression and levels of the anti-apoptotic Bcl-2 at both mRNA and protein levels, while significantly increase pro-apoptotic gene caspase-3 and Bax expression in the VX2 rabbit tumor models [117]. A subsequent prospective controlled clinical trial [118] demonstrated that the combination of ginsenoside Rg3 and TACE provided a greater survival benefit than TACE alone in patients with HCC. Additionally, the trial indicated that Rg3 alleviated some of the adverse syndromes and blood anomalies associated with TACE.

Several other anticancer drugs have also been found to improve the efficacy of TACE by influencing hypoxia signaling. The antitumor effects of arsenic trioxide (ATO)-loaded CSM-TACE have been investigated in VX2 HCC rabbit models. The results indicated that the expression of twist, N-calmodulin, waveform protein, and MMP-9 was decreased in the combined treatment group, while the expression of E-calmodulin was increased [119]. In models of VX2 liver xenograft tumor, the combination of rapamycin with TACE has also been demonstrated to exhibit anti-tumor neovascularization activity and to inhibit the expression levels of NOS, HIF-1a, VEGF, Bcl-2, and Bax. Arterial infusion of rapamycin was found to be more effective than intravenous injection, and large doses were observed to present better efficacy [120]. In addition, AMD3100, chemokine (C-X-C motif) receptor 4 (CXCR4) antagonist, was shown to enhance therapeutic efficacy of TACE (doxorubicinlipiodol emulsion) in rats with HCC. AMD3100 was found to reduce TACE-induced MVD in HCC tissues by decreasing the expression of HIF-1α and VEGF. Furthermore, it has been shown to promote apoptosis and reduce cell proliferation in HCC [121]. Repeated TACE-induced hepatic hypoxia was found to exacerbate the progression of fibrosis in the peritumoral liver tissue, which was associated with increased expression of carbon tetrachloride, HIF-1α, TGF-β-1, and VEGF. The progression of fibrosis and the deterioration of liver function subsequent to TACE may be mitigated and slowed by the HIF-1α inhibitor LW6 [122].

6.1.2. HIF-2

In the context of HIF, HIF-1α is primarily implicated in the acute hypoxic process of the tumor. In contrast, HIF-2α is actively involved in the chronic hypoxic process and exhibits a stronger prognostic correlation with TACE relative to HIF-1α [123]. Furthermore, it has been demonstrated that sorafenib downregulates HIF-1α expression, shifting the hypoxic response from HIF-1α- to HIF-2α-dependent pathway. This results in the up-regulation of HIF-2α, which renders hypoxic HCC cells insensitive to sorafenib and induces the expression of VEGF and cyclin D1 [124]. The role of HIF-2 may be underestimated, which may explain why trials of HIF-2 inhibitors in combination with TACE are relatively rare. A recent study [125] utilized multifunctional polyvinyl alcohol (PVA)/hyaluronic acid (HA)-based microspheres loaded with doxorubicin (DOX) and PT-2385, a potent HIF-2α inhibitor, to improve the treatment of HCC. The results showed that PT/DOX-MS can block tumor cells in the G2/M phase. The introduction of PT-2385 effectively suppresses the expression levels of HIF-2α in hypoxic HCC cells, thereby downregulating the expression levels of Cyclin D1, VEGF, and TGF-α. Additionally, the combination of DOX and PT-2385 can jointly inhibit the expression of VEGF. This suggests that HIF-2α may be an ideal target for TACE therapy.

Table 1. Summarize of the therapeutic strategies of TACE combined with HIF-related pathway inhibitors for HCC.

Table 1. Summarize of the therapeutic strategies of TACE combined with HIF-related pathway inhibitors for HCC.

Item	Year	Refs.	Mechanism	Targets affected	Cancer hallmark affected
HIF-1	2023	[112]	Melatonin could inhibit tumor cell proliferation and migration by targeting HIF-1α and VEGF-A.	HIF-1α	↓HIF-1α ↓VEGF-A ↓MMP-2 ↓MMP-9 ↑E-cadherin
	2020	[119]	HIF-1α, VEGF and microvessel density were decreased by the CSM-ATO.	HIF-1α	↓HIF-1α ↓VEGF ↓MVD ↓Twist ↓N-cadherin ↓Vimentin ↓MMP-9 ↑E-cadherin
	2021	[120]	Arterial instillation of rapamycin+TACE in treatment of rabbit hepatic xenograft tumors could reduce tumor neovascularization and inhibit iNOS, HIF-1α, VEGF, Bcl-2 protein expression.	HIF-1α	↓iNOS ↓HIF-1α ↓VEGF ↓Bcl-2
	2022	[121]	CXCR4 antagonist AMD3100 enhanced therapeutic efficacy of TACE in rats with HCC via promoting the HCC cell apoptosis, reducing cell proliferation, and inhibiting MVD.	HIF-1α CXCR4	↓HIF-1α ↓VEGF ↓CXCR4 ↓MVD ↓Proliferation ↑Apoptosis
	2015	[122]	HIF-1α inhibitor LW6 attenuated the hypoxia-induced fibrosis progression in vivo. HIF-1α by HIF-1α-siRNA significantly decreased expression of TGF-β1 and VEGF in hypoxic hepatocytes.	HIF-1α	↓HIF-1α ↓VEGF ↓TGF-β1 ↓Collagen I ↓α-SMA ↓Fibrosis
	2010	[113]	10-hydroxycamptothecin is a HIF-1α inhibitor.	HIF-1α	↓HIF-1α ↓VEGF ↓MVD
	2015	[114]	Liposomal curcumin could block HIF-1α-mediated angiogenesis.	HIF-1α	↓HIF-1α ↓VEGF ↓MVD
	2019	[115]	Curcumin liposome suppressed the HIF-1α and survivin levels and inhibited the angiogenesis in VX2 rabbits after TAE.	HIF-1α	↓HIF-1α ↓VEGF ↓MVD ↓Survivin ↓Proliferation ↑Apoptosis
	2013	[117]	Ginsenoside Rg3 combined with TAE could effectively inhibit tumor growth by inhibiting tumor angiogenesis and inducing cancer cell apoptosis.	VEGF	↓VEGF ↓CD31 ↓Angiogenesis ↑Caspase-3 ↑Bax
	2016	[118]	The combination of ginsenoside Rg3 and TACE provided a greater survival benefit than TACE alone in patients with HCC.	VEGF	↑Overall survival ↑Time to progression ↑Time to untreatable progression ↑Disease control rate
HIF-2	2022	[125]	PT-2385 could effectively inhibit the expression level of HIF-2α in hypoxic HCC cells, thereby down-regulating the expression levels of Cyclin D1, VEGF and TGF-α.	HIF-2α	↓HIF-2α ↓VEGF ↓TGF-α ↓Cyclin D1

6.2. Combination of Hypoxia-Activated Prodrugs and TACE

6.2.1. Tirapazamine

Tirapazamine (TPZ), a bioreductive agent, is preferentially toxic to hypoxic cells. Under hypoxic conditions, TPZ is metabolized by an intracellular reductase to form a highly reactive radical species capable of inducing DNA single- and double-strand breaks and chromosome aberrations, resulting in cell death. In the presence of oxygen, the TPZ radical is oxidized back to the parent molecule, thereby largely preventing radical-induced damage [126]. In 2011, Sonoda et al. [127] found that the combination of intraperitoneal TPZ and TAE with gelatin microspheres significantly reduced the tumor growth rate compared with TAE or TPZ treatment alone in the rabbit VX2 model. Subsequently, another study by Lin et al. [128] reported that the combination of intravenous TPZ and hepatic arterial ligation had synergistic tumor-killing activity against hepatocellular carcinoma (HCC) in HBx transgenic mice. The safety findings of the toxicological study by Liu et al. [129] involving rats supported the clinical usage of intraarterial injection of TPZ in combination with embolization. Several follow-ups Phase I trials [130,131] demonstrated the safety and tolerability of intraarterial TPZ with TAE/TACE for HCC, yielding promising tumor responses. Li et al. [8] prepared TPZ-loaded CalliSpheres microspheres (CSMTPZs) and found that CSMTPZ therapy exhibited advantages in terms of hypoxia-selected cytotoxicity, tumor apoptosis and necrosis, animal survival, and safety over the conventional combination of TPZ and TAE in the rabbit VX2 model.

6.2.2. TH-302

TH-302 (evofosfamide) is a 2-nitroimidazole triggered HAP of the cytotoxin bromo-isophosphoramide mustard [132]. The dinitroimidazole structure will be fragmented with an alkylating agent dibromoisophosphoramide mustard that selectively binds to the DNA and kills the tumor cells. Thus, it exerts little activity in the normoxic zone and fewer side effects on the normal tissues. TH-302 has shown broad-spectrum anticancer efficacy in multiple human cell lines and xenograft models [92,133,134,135,136,137]. In the rabbit VX2 model, Duran et al. [138] combined the cTACE and TH-302 by mixing the doxorubicin/Lipiodol emulsion and TH-302 followed by embolization with 100-300 μm bland beads. The results indicate that cTACE+TH-302 induced smaller tumor volumes, lower tumor growth rates, higher necrotic fractions, and exhibited no additional toxicity profile compared to cTACE. Another rabbit VX2 model by Ma et al. [139] involved the preparation of TH-302 loaded poly (lactic-co-glycolic acid) (PLGA)-based TACE microspheres. The results demonstrated that the TH-302 loaded microspheres exhibited sustained drug release in the liver tissue and superior anti-tumor efficacy in comparison to TH-302 injection and TH-302+lipiodol. Furthermore, no significant toxicity was observed throughout the treatment period.

Table 2. Summarize of the therapeutic strategies of TACE combined with hypoxia-activated prodrugs for HCC.

Table 2. Summarize of the therapeutic strategies of TACE combined with hypoxia-activated prodrugs for HCC.

Item	Year	Refs.	Mechanism	Targets affected	Cancer hallmark affected
Tirapazamine	2011	[127]	The combination of TPZ i.p. and GMS i.a. enhanced the antitumor effect of TPZ.	Hypoxic tumor	↓Tumor growth
	2016	[128]	At levels below the threshold oxygen levels created by HAL, TPZ was activated and killed the hypoxic cells, but spared the normoxic cells.	Hypoxic tumor	↑Necrosis ↑Apoptosis
	2021	[129]	The safety findings of this toxicological study involving rats supported the clinical usage of IA injection of TPZ in combination with embolization.	Hypoxic tumor	ALT Total bilirubin Histopathology
	2021	[131]	TPZ may be synergistic with TAE.	Hypoxic tumor	Tumor responses were evaluated using mRECIST criteria
	2022	[130]	TPZ i.a., in combination with TAE, was well tolerated and showed promising efficacy signals in intermediate-stage HCC.	Hypoxic tumor	Using the modified Response Evaluation Criteria in Solid Tumors
	2022	[8]	TPZ may exert synergistic tumor-killing activity with TAE for liver cancer.	Hypoxic tumor	↑Necrosis ↑Apoptosis
TH302	2017	[138]	Evofosfamide in combination with cTACE enhanced anticancer effects.	Hypoxic tumor	↓Ki-67 ↑γ-H2A.X ↑annexin V ↑caspase-3 ↑Apoptosis
	2020	[139]	TH-302 is a hypoxia-activated prodrug targeting the intra-tumoral hypoxic environment.	Hypoxic tumor	↑Necrosis ↑Apoptosis

6.3. Combination of Gene Therapy and TACE

6.3.1. Hypoxia Pathway-Related Gene Therapy

RNA modulation is a common modality for HIF-related gene therapy. Previous studies have proposed the use of RNA interference (RNAi) of HIF-1α to enhance the efficacy of TAE in the treatment of HCC. RNAi is a process whereby the expression of specific genes is silenced by the introduction of small interfering RNAs (siRNAs), endogenous miRs, and other short double-stranded RNAs [140]. The study by Chen et al. [141] has confirmed that RNAi of HIF-1α improves the efficacy of TAE in the treatment of HCC. Its resulting HIF-1α silencing effectively inhibits the increase in VEGF expression and MVD after TAE, inhibits liver tumor growth, and reduces the number of lung metastases. The results of their subsequent study [142], which employed ultrasound-guided HIF-1α RNAi, demonstrated an improvement in the efficacy of TACE in the treatment of HCC, thereby further confirming previous findings. Moreover, the study by Ni et al. [143] yielded comparable outcomes. In this study, the iodized oil emulsion was prepared by combining lipiodol with a siRNA transfection compound, which was then delivered via the hepatic artery during the TAE procedure. In the rabbit VX2 model by Guo et al. [144], the TAE with drug-free microspheres combined with intraarterial transfecting HIF-1α shRNA on HCC demonstrated superior anti-tumor efficacy compared to monotherapy.

The combination of TACE with HIF-related gene knockdown represents a promising therapeutic approach for the treatment of HCC. Liu et al. [145] found that the myocardial infarction associated transcript (MIAT)/microRNA (miR)-203a/HIF-1α axis could affect the efficacy of TAE. MIAT and HIF-1α were highly expressed and miR-203a was lowly expressed in hypoxia-stimulated hepatocellular carcinoma cells after TACE. MIAT gene regulated the miR-203a/HIF-1α axis, and MIAT knockdown enhanced TAE-mediated antitumor effects by upregulating MIR-203a and downregulating HIF-1α. In addition, the lentiviral delivery (LV-H721) of the CRISPR/Cas9 protein and an HIF-1α-specific sgRNA resulted in highly efficient HIF-1α modification. A study employed CRISPR/Cas9-mediated knockdown of HIF-1α [146]. The results demonstrated that lentiviral delivery of CRISPR/Cas9 protein and HIF-1α-specific sgRNA was an effective method for modifying HIF-1α. Furthermore, the combination of CRISPR/Cas9-mediated HIF-1α knockdown and TAE was found to significantly suppress tumors and prolong the survival time of HCC mice.

6.3.2. Hypoxia-Targeted Oncolytic Virus

In 2008, Altomonte et al. [147] proposed a novel method of treatment for HCC in rats, termed viroembolization. This approach involved the co-administration of recombinant vesicular stomatitis virus (VSV) with degradable starch microspheres (DSM), which were injected through the hepatic artery. The researchers observed that viral embolization induced apoptosis in tumor margins that survived embolization, significantly reducing intratumoral CD31 staining. Additionally, the procedure prevented neointimal formation after embolization, recruited NK cells and CD8+ T cells to infiltrate, and led to massive tumor necrosis. The study by Sun et al. [148] demonstrated for the first time that portal infusion of adeno-associated viral vectors expressing antisense HIF1-α downregulated HIF-1a and its downstream effectors, including vascular endothelial growth factor, GLUT1, and LDHA, and enhanced the inhibitory effect of TAE on the growth of HCC in rats. Zhang et al. [149] synthesized a hypoxia-replicative oncolytic adenovirus (HYAD) and constructed VX2 HCC rabbit models by HYAD perfusion combined with polyvinyl alcohol (PVA) embolization. The results showed that in vitro experiments demonstrated that HYAD was expressed and replicated in the presence of HIF-1α expression or hypoxia. In the in vivo experiments in the VX2 model, HYAD perfusion combined with PVA embolization resulted in the highest expression and the longest expression duration compared with HYAD perfusion alone, wild adenovirus type 5 (WT) perfusion combined with PVA embolization, and WT perfusion alone.

In another aspect, data from a rabbit VX2 tumor model found that transarterial viroembolization (TAVE) has been demonstrated the most effective modality with more homogeneous oncolytic virus distribution and therapeutic efficacy compared to other routes of administration via transarterial viral infusion, commonly used intratumoral injection and intravenous injection. TAVE is the optimal and safe therapy for the treatment of immune-refractory HCC, and the synergistic effect achieves significant tumor response, standby effect, survival benefit and anti-tumor immune memory, providing an innovative therapeutic approach for clinical practice [150]. It has to be acknowledged that the combination of TACE and oncolytic virus shows great promise, whether targeting hypoxic tumor cells or not.

Table 3. Summarize of the therapeutic strategies of TACE combined with gene therapy for HCC.

Table 3. Summarize of the therapeutic strategies of TACE combined with gene therapy for HCC.

Item	Year	Refs.	Mechanism	Targets affected	Cancer hallmark affected
Hypoxia pathway-related gene therapy	2012	[141]	HIF-1α RNAi visibly reduced the expression of HIF-1α and vascular endothelial growth factor, suppressed tumor angiogenesis, and attenuated metastasis.	HIF-1α	↓HIF-1α ↓VEGF ↓MVD
	2015	[142]	HIF-1α RNAi could downregulate the levels of HIF-1α and VEGF, inhibit tumor angiogenesis, and lessen metastases.	HIF-1α	↓HIF-1α ↓VEGF ↓MVD
	2017	[143]	HIF-1α-siRNA could inhibit the expression levels of HIF-1α and VEGF effectively.	HIF-1α	↓HIF-1α ↓VEGF
	2020	[144]	HIF-1α shRNA could decrease the formation of blood vessels, slow tumor growth, reduce tumor size and promote tumor cell apoptosis.	HIF-1α	↓HIF-1α ↓VEGF ↓CD34
	2020	[145]	MIAT knockdown potentiated the therapeutic effect of TAE in liver cancer by regulating the miR-203a/HIF-1α axis in vitro and in vivo.	MIAT/ miR-203a/ HIF-1α	↑miR-203a ↓HIF-1α
	2018	[146]	The combination of CRISPR/Cas9-mediated HIF-1a knockdown and TAE was found to significantly suppress tumors.	HIF-1α	↓HIF-1α ↓CD31 ↓Invasiveness ↓Migration ↓Proliferation ↑Apoptosis
Hypoxia-targeted oncolytic virus	2008	[147]	Viral embolization induced apoptosis in tumor margins that survived embolization, significantly reducing intratumoral CD31 staining.	Hypoxic tumor	↓CD31 ↓Proliferation ↑Apoptosis ↑Necrosis
	2009	[148]	Intraportal delivery of adeno-associated viral vectors expressing antisense HIF-α augmented TAE to combat hepatocellular carcinoma.	HIF-1α	↓HIF-1α ↓VEGF ↓GLUT1 ↓LDHA ↓Proliferation ↑Apoptosis
	2019	[149]	Adenovirus expression protein E1A has the properties of promoting apoptosis, inhibiting invasion, and inhibiting metastasis.	Hypoxic tumor	↓Proliferation ↓Migration ↑Apoptosis
	2023	[150]	TAVE modified the immune cell densities for immune-excluded liver cancer, partially destroyed vessel metastases, and established antitumor immune memory.	Tumor cells	↓Proliferation ↑Apoptosis ↑Necrosis

6.4. Combination of Other or Novel Therapies and TACE

6.4.1. Metabolic Reprogram

Metabolic reprogramming combined with TACE is an emerging cancer treatment strategy that enhances efficacy by simultaneously disrupting tumor metabolism and blocking tumor blood supply. 3-Bromopyruvate (3-BrPA) is one of the early promising anti-glycolytic drugs. Early studies have found that 3-BrPA combined with TAE/TACE shows limited efficacy [151,152].

A study was conducted by Wilkins et al. [153] to assess the efficacy of TAE in combination with two cinnamic acid derivatives, caffeic acid (CA) or ferulic acid (FA), in a rat model of N1-S1 HCC. The results demonstrated that CA and FA resulted in a significant reduction of lactate efflux from N1S1 tumor cells by more than 90% (P < 0.01). Additionally, pathological assessment revealed the absence of residual live tumor cells in the TAE+CA and TAE+FA groups, accompanied by a notable reduction in tumor volume compared to TAE.

Bumetanide (BU) is a fast-acting, short-duration loop diuretic. In addition, BU blocks the rate-limiting step of phosphofructokinase in anaerobic glycolysis. A study [154] demonstrated a significant increase in tumor necrosis in N1-S1 HCC treated with TAE in combination with BU, with tumor volume reduced by 18.2 ± 12.2%. The TAE group demonstrated a reduction of 90.4 ± 10.2%, while the TAE+BU group exhibited a 72.2% reduction compared to the TAE-only group (P < 0.0001). Additionally, histopathological evaluation revealed the absence of residual tumor tissue in the TAE+BU group.

PKM2 is a splice variant of pyruvate kinase. It has been implicated in the propagation of the Warburg effect in cancer cell metabolism. Martin et al. [155] found that PKM2 is associated with chemotherapy and TACE resistance. Inhibition of PKM2 by gene silencing or the agent shikonin allows for targeted therapeutic reprogramming to overcome resistance, thereby reversing TACE resistance to improve TACE efficacy.

A study [156] evaluated the antitumor effects of the LDHA inhibitor sodium oxalate (Ox) in combination with TACE and the underlying mechanisms using the rabbit VX2 liver tumor model. The results demonstrated that Ox + TACE downregulated VEGF and matrix metalloproteinase-9 (MMP-9) and enhanced the infiltration of CD3+ and CD8+ T cells into tumor tissues, significantly improving the antitumor effect.

6.4.2. Mitochondrial Autophagy

Targeting of mitochondrial fission and mitophagy is a novel therapeutic approach to HCC. Ischemia induces mitochondrial autophagy to maintain nutrients and energy in the short term and to limit short-term damage. However, in the long term, this process transforms into a self-destructive process that ultimately leads to cell death. Mitochondrial autophagy removes damaged mitochondria and promotes the survival of HCC cells [157].

Lin et al. [158] demonstrated that the mitochondrial fission and mitophagy, which are mediated by dynamin-related protein 1 (DRP1), were significantly enhanced in surviving HCC cells under hypoxic conditions when subjected to in vitro simulation of the conditions that occur after TACE. Moreover, Mdivi-1, an inhibitor of DRP1, suppressed hypoxic HCC growth in vivo. Therefore, combined blockade of DRP1 is a potential approach to improve the efficacy of TAE/TACE therapy.

Zhong et al. [159] found that TACE induces S100 calcium binding protein A9 (S100A9), a key oncogene involved in post-TACE progression, via the HIF-1α-mediated pathway. S100A9 promotes the growth and metastasis of HCC by causing the deubiquitination and stabilization of PGAM5 and leading to mitochondrial fission and ROS production.

Furthermore, mitophagy has been found to be blocked by the combination of sorafenib with glucose restriction, thus suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC [160].

Table 4. Summarize of the therapeutic strategies of TACE combined with other or novel therapies for HCC.

Table 4. Summarize of the therapeutic strategies of TACE combined with other or novel therapies for HCC.

Item	Year	Refs.	Mechanism	Targets affected	Cancer hallmark affected
Metabolic reprogram	2002	[151]	3-bromopyruvate is a potent inhibitorof cell ATP production.	Tumor cells	↑Necrosis ×Migration
	2008	[152]	3-BrPA acts as an irreversible inhibitor of glycolytic enzymes.	Tumor cells	↑Necrosis ×Migration
	2017	[153]	CA or FA enhanced the effectiveness of TAE therapy for HCC in part by blocking lactate efflux.	Anaerobic metabolism/ lactate	↓ECAR ↓MCT4 ↑Necrosis
	2017	[154]	Bumetanide is a glycolytic metabolism pathway inhibitor.	Glycolysis	↑Necrosis
	2020	[155]	Shikonin, a naphthoquinone, has been shown to inhibit glycolysis through PKM2 specific inhibition.	PKM2 Glycolysis	↑Necrosis ↓Migration ↓Proliferation ↓Lactat
	2024	[156]	Ox could inhibit LDHA and the Warburg effect.	Aerobic glycolysis	↓MMP-9 ↓VEGF ↑Apoptosis ↑CD3+T ↑CD8+T
Mitochondrial autophagy	2024	[158]	Blocking DRP1-mediated mitochondrial fission and mitophagy increased the incidence of mitochondrial apoptosis of HCC cells during hypoxia.	Mitochondrial mitophagy	↑Mitochondrial apoptosis ↑Apoptosis-inducing factor ↑Cytochrome c ↓Mitochondrial membrane potential
	2022	[159]	Depletion or pharmacologic inhibition of S100A9 significantly dampened the growth and metastatic ability of HCC.	Mitochondrial S100A9	↓Mitochondrial fission ↓ROS production ↓EMT programs
	2022	[160]	Sorafenib and glucose restriction exacerbated mitochondrial damage and ultimately caused cell death.	Mitochondrial mitophagy Glycolysis	↓ATP ↓OCR ↓Mitochondrial mitophagy ↑Necrosis

7. Conclusions

References

1. Vogel, A.; Meyer, T.; Sapisochin, G.; Salem, R.; Saborowski, A. Hepatocellular carcinoma. Lancet 2022, 400, 1345–1362. [Google Scholar] [CrossRef] [PubMed]
2. Reig, M.; Forner, A.; Rimola, J.; Ferrer-Fabrega, J.; Burrel, M.; Garcia-Criado, A.; Kelley, R.K.; Galle, P.R.; Mazzaferro, V.; Salem, R.; et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022, 76, 681–693. [Google Scholar] [CrossRef] [PubMed]
3. Zeng, H.; Chen, W.; Zheng, R.; Zhang, S.; Ji, J.S.; Zou, X.; Xia, C.; Sun, K.; Yang, Z.; Li, H.; et al. Changing cancer survival in China during 2003-15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health 2018, 6, e555–e567. [Google Scholar] [CrossRef] [PubMed]
4. Park, J.-W.; Chen, M.; Colombo, M.; Roberts, L.R.; Schwartz, M.; Chen, P.-J.; Kudo, M.; Johnson, P.; Wagner, S.; Orsini, L.S.; et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int 2015, 35, 2155–2166. [Google Scholar] [CrossRef] [PubMed]
5. Galle, P.R.; Forner, A.; Llovet, J.M.; Mazzaferro, V.; Piscaglia, F.; Raoul, J.-L.; Schirmacher, P.; Vilgrain, V. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology 2018, 69, 182–236. [Google Scholar] [CrossRef] [PubMed]
6. Höckel, M.; Vaupel, P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001, 93, 266–276. [Google Scholar] [CrossRef] [PubMed]
7. Yasuda, S.; Arii, S.; Mori, A.; Isobe, N.; Yang, W.; Oe, H.; Fujimoto, A.; Yonenaga, Y.; Sakashita, H.; Imamura, M. Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance. Journal of Hepatology 2004, 40, 117–123. [Google Scholar] [CrossRef] [PubMed]
8. Li, Q.; Liu, Y.; Guo, X.; Zhang, L.; Li, L.; Zhao, D.; Zhang, X.; Hong, W.; Zheng, C.; Liang, B. Tirapazamine-loaded CalliSpheres microspheres enhance synergy between tirapazamine and embolization against liver cancer in an animal model. Biomed Pharmacother 2022, 151, 113123. [Google Scholar] [CrossRef] [PubMed]
9. Suzuki, H.; Mori, M.; Kawaguchi, C.; Adachi, M.; Miura, S.; Ishii, H. Serum vascular endothelial growth factor in the course of transcatheter arterial embolization of hepatocellular carcinoma. International Journal of Oncology 1999, 14, 1087–1090. [Google Scholar] [CrossRef]
10. Li, X.; Feng, G.-S.; Zheng, C.-S.; Zhuo, C.-K.; Liu, X. Influence of transarterial chemoembolization on angiogenesis and expression of vascular endothelial growth factor and basic fibroblast growth factor in rat with Walker-256 transplanted hepatoma: an experimental study. World Journal of Gastroenterology 2003, 9, 2445–2449. [Google Scholar] [CrossRef]
11. Shao, G.; Wang, J.; Zhou, K.; Yan, Z. Intratumoral microvessel density and expression of vascular endothelial growth factor in hepatocellular carcinoma after chemoembolization. Zhonghua Gan Zang Bing Za Zhi 2002, 10, 170–173. [Google Scholar] [PubMed]
12. Gupta, S.; Kobayashi, S.; Phongkitkarun, S.; Broemeling, L.D.; Kan, Z. Effect of transcatheter hepatic arterial embolization on angiogenesis in an animal model. Investigative Radiology 2006, 41, 516–521. [Google Scholar] [CrossRef] [PubMed]
13. Liang, B.; Zheng, C.S.; Feng, G.S.; Wu, H.P.; Wang, Y.; Zhao, H.; Qian, J.; Liang, H.M. Correlation of hypoxia-inducible factor 1alpha with angiogenesis in liver tumors after transcatheter arterial embolization in an animal model. Cardiovasc Intervent Radiol 2010, 33, 806–812. [Google Scholar] [CrossRef] [PubMed]
14. Petrillo, M.; Patella, F.; Pesapane, F.; Suter, M.B.; Ierardi, A.M.; Angileri, S.A.; Floridi, C.; de Filippo, M.; Carrafiello, G. Hypoxia and tumor angiogenesis in the era of hepatocellular carcinoma transarterial loco-regional treatments. Future Oncology (London, England) 2018, 14, 2957–2967. [Google Scholar] [CrossRef] [PubMed]
15. Ye, Y.; Hu, Q.; Chen, H.; Liang, K.; Yuan, Y.; Xiang, Y.; Ruan, H.; Zhang, Z.; Song, A.; Zhang, H.; et al. Characterization of Hypoxia-associated Molecular Features to Aid Hypoxia-Targeted Therapy. Nat Metab 2019, 1, 431–444. [Google Scholar] [CrossRef] [PubMed]
16. Sin, S.Q.; Mohan, C.D.; Goh, R.M.W.-J.; You, M.; Nayak, S.C.; Chen, L.; Sethi, G.; Rangappa, K.S.; Wang, L. Hypoxia signaling in hepatocellular carcinoma: Challenges and therapeutic opportunities. Cancer Metastasis Reviews 2023, 42, 741–764. [Google Scholar] [CrossRef] [PubMed]
17. Guo, Y.; Xiao, Z.; Yang, L.; Gao, Y.; Zhu, Q.; Hu, L.; Huang, D.; Xu, Q. Hypoxia-inducible factors in hepatocellular carcinoma (Review). Oncology Reports 2020, 43. [Google Scholar] [CrossRef] [PubMed]
18. Emami Nejad, A.; Najafgholian, S.; Rostami, A.; Sistani, A.; Shojaeifar, S.; Esparvarinha, M.; Nedaeinia, R.; Haghjooy Javanmard, S.; Taherian, M.; Ahmadlou, M.; et al. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int 2021, 21, 62. [Google Scholar] [CrossRef] [PubMed]
19. Luo, Z.; Tian, M.; Yang, G.; Tan, Q.; Chen, Y.; Li, G.; Zhang, Q.; Li, Y.; Wan, P.; Wu, J. Hypoxia signaling in human health and diseases: implications and prospects for therapeutics. Signal Transduct Target Ther 2022, 7, 218. [Google Scholar] [CrossRef]
20. Chen, Z.; Han, F.; Du, Y.; Shi, H.; Zhou, W. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther 2023, 8, 70. [Google Scholar] [CrossRef]
21. Tümen, D.; Heumann, P.; Gülow, K.; Demirci, C.-N.; Cosma, L.-S.; Müller, M.; Kandulski, A. Pathogenesis and Current Treatment Strategies of Hepatocellular Carcinoma. Biomedicines 2022, 10. [Google Scholar] [CrossRef] [PubMed]
22. Cairns, R.A.; Hill, R.P. Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res 2004, 64, 2054–2061. [Google Scholar] [CrossRef] [PubMed]
23. Hammond, E.M.; Dorie, M.J.; Giaccia, A.J. ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. J Biol Chem 2003, 278, 12207–12213. [Google Scholar] [CrossRef] [PubMed]
24. Chan, N.; Bristow, R.G. “Contextual” synthetic lethality and/or loss of heterozygosity: tumor hypoxia and modification of DNA repair. Clin Cancer Res 2010, 16, 4553–4560. [Google Scholar] [CrossRef] [PubMed]
25. Mathieu, J.; Zhang, Z.; Nelson, A.; Lamba, D.A.; Reh, T.A.; Ware, C.; Ruohola-Baker, H. Hypoxia induces re-entry of committed cells into pluripotency. Stem Cells 2013, 31, 1737–1748. [Google Scholar] [CrossRef] [PubMed]
26. De Francesco, E.M.; Lappano, R.; Santolla, M.F.; Marsico, S.; Caruso, A.; Maggiolini, M. HIF-1α/GPER signaling mediates the expression of VEGF induced by hypoxia in breast cancer associated fibroblasts (CAFs). Breast Cancer Res 2013, 15, R64. [Google Scholar] [CrossRef] [PubMed]
27. Santhakumar, C.; Gane, E.J.; Liu, K.; McCaughan, G.W. Current perspectives on the tumor microenvironment in hepatocellular carcinoma. Hepatol Int 2020, 14, 947–957. [Google Scholar] [CrossRef] [PubMed]
28. Wang, X.; Mao, J.; Zhou, T.; Chen, X.; Tu, H.; Ma, J.; Li, Y.; Ding, Y.; Yang, Y.; Wu, H.; et al. Hypoxia-induced myeloid derived growth factor promotes hepatocellular carcinoma progression through remodeling tumor microenvironment. Theranostics 2021, 11, 209–221. [Google Scholar] [CrossRef]
29. Yang, M.H.; Mohan, C.D.; Deivasigamani, A.; Chinnathambi, A.; Alharbi, S.A.; Rangappa, K.S.; Jung, S.H.; Ko, H.; Hui, K.M.; Sethi, G.; et al. Procaine Abrogates the Epithelial-Mesenchymal Transition Process through Modulating c-Met Phosphorylation in Hepatocellular Carcinoma. Cancers 2022, 14. [Google Scholar] [CrossRef]
30. Jung, Y.Y.; Mohan, C.D.; Eng, H.; Narula, A.S.; Namjoshi, O.A.; Blough, B.E.; Rangappa, K.S.; Sethi, G.; Kumar, A.P.; Ahn, K.S. 2,3,5,6-Tetramethylpyrazine Targets Epithelial-Mesenchymal Transition by Abrogating Manganese Superoxide Dismutase Expression and TGFβ-Driven Signaling Cascades in Colon Cancer Cells. Biomolecules 2022, 12. [Google Scholar] [CrossRef]
31. Gurzu, S.; Kobori, L.; Fodor, D.; Jung, I. Epithelial Mesenchymal and Endothelial Mesenchymal Transitions in Hepatocellular Carcinoma: A Review. Biomed Res Int 2019, 2019, 2962580. [Google Scholar] [CrossRef] [PubMed]
32. Willis, B.C.; Liebler, J.M.; Luby-Phelps, K.; Nicholson, A.G.; Crandall, E.D.; du Bois, R.M.; Borok, Z. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol 2005, 166, 1321–1332. [Google Scholar] [CrossRef] [PubMed]
33. Copple, B.L. Hypoxia stimulates hepatocyte epithelial to mesenchymal transition by hypoxia-inducible factor and transforming growth factor-beta-dependent mechanisms. Liver Int 2010, 30, 669–682. [Google Scholar] [CrossRef] [PubMed]
34. Erler, J.T.; Giaccia, A.J. Lysyl oxidase mediates hypoxic control of metastasis. Cancer Res 2006, 66, 10238–10241. [Google Scholar] [CrossRef] [PubMed]
35. Zhang, Q.; Bai, X.; Chen, W.; Ma, T.; Hu, Q.; Liang, C.; Xie, S.; Chen, C.; Hu, L.; Xu, S.; et al. Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1α signaling. Carcinogenesis 2013, 34, 962–973. [Google Scholar] [CrossRef] [PubMed]
36. Dou, C.; Zhou, Z.; Xu, Q.; Liu, Z.; Zeng, Y.; Wang, Y.; Li, Q.; Wang, L.; Yang, W.; Liu, Q.; et al. Hypoxia-induced TUFT1 promotes the growth and metastasis of hepatocellular carcinoma by activating the Ca2+/PI3K/AKT pathway. Oncogene 2019, 38, 1239–1255. [Google Scholar] [CrossRef] [PubMed]
37. Amelio, I.; Inoue, S.; Markert, E.K.; Levine, A.J.; Knight, R.A.; Mak, T.W.; Melino, G. TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation. Proc Natl Acad Sci U S A 2015, 112, 226–231. [Google Scholar] [CrossRef]
38. Liu, Z.; Wang, Y.; Dou, C.; Xu, M.; Sun, L.; Wang, L.; Yao, B.; Li, Q.; Yang, W.; Tu, K.; et al. Hypoxia-induced up-regulation of VASP promotes invasiveness and metastasis of hepatocellular carcinoma. Theranostics 2018, 8, 4649–4663. [Google Scholar] [CrossRef]
39. Chen, Z.; Zuo, X.; Zhang, Y.; Han, G.; Zhang, L.; Wu, J.; Wang, X. MiR-3662 suppresses hepatocellular carcinoma growth through inhibition of HIF-1α-mediated Warburg effect. Cell Death Dis 2018, 9, 549. [Google Scholar] [CrossRef]
40. Ma, S.; Zhao, Y.; Lee, W.C.; Ong, L.-T.; Lee, P.L.; Jiang, Z.; Oguz, G.; Niu, Z.; Liu, M.; Goh, J.Y.; et al. Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy. Nat Commun 2022, 13, 4118. [Google Scholar] [CrossRef]
41. Zhu, H.; Chen, X.P.; Luo, S.F.; Guan, J.; Zhang, W.G.; Zhang, B.X. Involvement of hypoxia-inducible factor-1-alpha in multidrug resistance induced by hypoxia in HepG2 cells. J Exp Clin Cancer Res 2005, 24, 565–574. [Google Scholar]
42. Wartenberg, M.; Ling, F.C.; Müschen, M.; Klein, F.; Acker, H.; Gassmann, M.; Petrat, K.; Pütz, V.; Hescheler, J.; Sauer, H. Regulation of the multidrug resistance transporter P-glycoprotein in multicellular tumor spheroids by hypoxia-inducible factor (HIF-1) and reactive oxygen species. FASEB J 2003, 17, 503–505. [Google Scholar] [CrossRef]
43. Teicher, B.A. Hypoxia and drug resistance. Cancer Metastasis Reviews 1994, 13, 139–168. [Google Scholar] [CrossRef]
44. Lee, P.; Chandel, N.S.; Simon, M.C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat Rev Mol Cell Biol 2020, 21, 268–283. [Google Scholar] [CrossRef]
45. Liao, C.; Liu, X.; Zhang, C.; Zhang, Q. Tumor hypoxia: From basic knowledge to therapeutic implications. Semin Cancer Biol 2023, 88, 172–186. [Google Scholar] [CrossRef] [PubMed]
46. Wu, Q.; Zhou, W.; Yin, S.; Zhou, Y.; Chen, T.; Qian, J.; Su, R.; Hong, L.; Lu, H.; Zhang, F.; et al. Blocking Triggering Receptor Expressed on Myeloid Cells-1-Positive Tumor-Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti-Programmed Cell Death Ligand 1 Resistance in Liver Cancer. Hepatology 2019, 70, 198–214. [Google Scholar] [CrossRef]
47. Yuen, V.W.-H.; Wong, C.C.-L. Hypoxia-inducible factors and innate immunity in liver cancer. J Clin Invest 2020, 130, 5052–5062. [Google Scholar] [CrossRef]
48. Fu, Y.; Liu, S.; Zeng, S.; Shen, H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res 2019, 38, 396. [Google Scholar] [CrossRef] [PubMed]
49. Bailey, C.M.; Liu, Y.; Liu, M.; Du, X.; Devenport, M.; Zheng, P.; Liu, Y.; Wang, Y. Targeting HIF-1α abrogates PD-L1-mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues. J Clin Invest 2022, 132. [Google Scholar] [CrossRef] [PubMed]
50. Warburg, O. On the origin of cancer cells. Science 1956, 123, 309–314. [Google Scholar] [CrossRef]
51. Keith, B.; Johnson, R.S.; Simon, M.C. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nature Reviews. Nature Reviews. Cancer 2011, 12. [Google Scholar] [CrossRef]
52. Gwak, G.-Y.; Yoon, J.-H.; Kim, K.M.; Lee, H.-S.; Chung, J.W.; Gores, G.J. Hypoxia stimulates proliferation of human hepatoma cells through the induction of hexokinase II expression. Journal of Hepatology 2005, 42, 358–364. [Google Scholar] [CrossRef] [PubMed]
53. Bao, M.H.-R.; Wong, C.C.-L. Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer. Cells 2021, 10. [Google Scholar] [CrossRef] [PubMed]
54. Niu, Y.; Lin, Z.; Wan, A.; Sun, L.; Yan, S.; Liang, H.; Zhan, S.; Chen, D.; Bu, X.; Liu, P.; et al. Loss-of-Function Genetic Screening Identifies Aldolase A as an Essential Driver for Liver Cancer Cell Growth Under Hypoxia. Hepatology 2021, 74, 1461–1479. [Google Scholar] [CrossRef] [PubMed]
55. Schito, L.; Semenza, G.L. Hypoxia-Inducible Factors: Master Regulators of Cancer Progression. Trends Cancer 2016, 2, 758–770. [Google Scholar] [CrossRef] [PubMed]
56. Yu, H.; He, J.; Liu, W.; Feng, S.; Gao, L.; Xu, Y.; Zhang, Y.; Hou, X.; Zhou, Y.; Yang, L.; et al. The Transcriptional Coactivator, ALL1-Fused Gene From Chromosome 9, Simultaneously Sustains Hypoxia Tolerance and Metabolic Advantages in Liver Cancer. Hepatology 2021, 74, 1952–1970. [Google Scholar] [CrossRef] [PubMed]
57. Miao, B.; Wei, C.; Qiao, Z.; Han, W.; Chai, X.; Lu, J.; Gao, C.; Dong, R.; Gao, D.; Huang, C.; et al. eIF3a mediates HIF1α-dependent glycolytic metabolism in hepatocellular carcinoma cells through translational regulation. Am J Cancer Res 2019, 9, 1079–1090. [Google Scholar] [PubMed]
58. Dong, F.; Li, R.; Wang, J.; Zhang, Y.; Yao, J.; Jiang, S.-H.; Hu, X.; Feng, M.; Bao, Z. Hypoxia-dependent expression of MAP17 coordinates the Warburg effect to tumor growth in hepatocellular carcinoma. J Exp Clin Cancer Res 2021, 40, 121. [Google Scholar] [CrossRef]
59. Yang, N.; Wang, T.; Li, Q.; Han, F.; Wang, Z.; Zhu, R.; Zhou, J. HBXIP drives metabolic reprogramming in hepatocellular carcinoma cells via METTL3-mediated m6A modification of HIF-1α. J Cell Physiol 2021, 236, 3863–3880. [Google Scholar] [CrossRef]
60. Zhou, Y.; Huang, Y.; Hu, K.; Zhang, Z.; Yang, J.; Wang, Z. HIF1A activates the transcription of lncRNA RAET1K to modulate hypoxia-induced glycolysis in hepatocellular carcinoma cells via miR-100-5p. Cell Death Dis 2020, 11, 176. [Google Scholar] [CrossRef]
61. Hu, M.; Fu, Q.; Jing, C.; Zhang, X.; Qin, T.; Pan, Y. LncRNA HOTAIR knockdown inhibits glycolysis by regulating miR-130a-3p/HIF1A in hepatocellular carcinoma under hypoxia. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 2020, 125, 109703. [Google Scholar] [CrossRef]
62. Ramsey, D.E.; Kernagis, L.Y.; Soulen, M.C.; Geschwind, J.-F.H. Chemoembolization of hepatocellular carcinoma. Journal of Vascular and Interventional Radiology : JVIR 2002, 13, S211–S221. [Google Scholar] [CrossRef]
63. Gaba, R.C.; Lokken, R.P.; Hickey, R.M.; Lipnik, A.J.; Lewandowski, R.J.; Salem, R.; Brown, D.B.; Walker, T.G.; Silberzweig, J.E.; Baerlocher, M.O.; et al. Quality Improvement Guidelines for Transarterial Chemoembolization and Embolization of Hepatic Malignancy. Journal of Vascular and Interventional Radiology : JVIR. [CrossRef]
64. Geschwind, J.-F.H. Chemoembolization for hepatocellular carcinoma: where does the truth lie? Journal of Vascular and Interventional Radiology : JVIR 2002, 13, 991–994. [Google Scholar] [CrossRef]
65. Llovet, J.M.; Real, M.I.; Montaña, X.; Planas, R.; Coll, S.; Aponte, J.; Ayuso, C.; Sala, M.; Muchart, J.; Solà, R.; et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002, 359, 1734–1739. [Google Scholar] [CrossRef]
66. Lo, C.-M.; Ngan, H.; Tso, W.-K.; Liu, C.-L.; Lam, C.-M.; Poon, R.T.-P.; Fan, S.-T.; Wong, J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002, 35, 1164–1171. [Google Scholar] [CrossRef] [PubMed]
67. Lencioni, R.; de Baere, T.; Soulen, M.C.; Rilling, W.S.; Geschwind, J.-F.H. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: A systematic review of efficacy and safety data. Hepatology 2016, 64, 106–116. [Google Scholar] [CrossRef] [PubMed]
68. Gaba, R.C.; Lewandowski, R.J.; Hickey, R.; Baerlocher, M.O.; Cohen, E.I.; Dariushnia, S.R.; Janne d’Othée, B.; Padia, S.A.; Salem, R.; Wang, D.S.; et al. Transcatheter Therapy for Hepatic Malignancy: Standardization of Terminology and Reporting Criteria. Journal of Vascular and Interventional Radiology : JVIR 2016, 27, 457–473. [Google Scholar] [CrossRef]
69. Lammer, J.; Malagari, K.; Vogl, T.; Pilleul, F.; Denys, A.; Watkinson, A.; Pitton, M.; Sergent, G.; Pfammatter, T.; Terraz, S.; et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovascular and Interventional Radiology 2010, 33, 41–52. [Google Scholar] [CrossRef] [PubMed]
70. Malagari, K.; Pomoni, M.; Moschouris, H.; Bouma, E.; Koskinas, J.; Stefaniotou, A.; Marinis, A.; Kelekis, A.; Alexopoulou, E.; Chatziioannou, A.; et al. Chemoembolization with doxorubicin-eluting beads for unresectable hepatocellular carcinoma: five-year survival analysis. Cardiovascular and Interventional Radiology 2012, 35, 1119–1128. [Google Scholar] [CrossRef]
71. Song, M.J.; Chun, H.J.; Song, D.S.; Kim, H.Y.; Yoo, S.H.; Park, C.-H.; Bae, S.H.; Choi, J.Y.; Chang, U.I.; Yang, J.M.; et al. Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. Journal of Hepatology 2012, 57, 1244–1250. [Google Scholar] [CrossRef]
72. Golfieri, R.; Giampalma, E.; Renzulli, M.; Cioni, R.; Bargellini, I.; Bartolozzi, C.; Breatta, A.D.; Gandini, G.; Nani, R.; Gasparini, D.; et al. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer 2014, 111, 255–264. [Google Scholar] [CrossRef] [PubMed]
73. Facciorusso, A.; Di Maso, M.; Muscatiello, N. Drug-eluting beads versus conventional chemoembolization for the treatment of unresectable hepatocellular carcinoma: A meta-analysis. Dig Liver Dis 2016, 48, 571–577. [Google Scholar] [CrossRef] [PubMed]
74. Harris, A.L. Hypoxia--a key regulatory factor in tumour growth. Nature Reviews. Cancer 2002, 2, 38–47. [Google Scholar] [PubMed]
75. Virmani, S.; Rhee, T.K.; Ryu, R.K.; Sato, K.T.; Lewandowski, R.J.; Mulcahy, M.F.; Kulik, L.M.; Szolc-Kowalska, B.; Woloschak, G.E.; Yang, G.Y.; et al. Comparison of hypoxia-inducible factor-1alpha expression before and after transcatheter arterial embolization in rabbit VX2 liver tumors. J Vasc Interv Radiol 2008, 19, 1483–1489. [Google Scholar] [CrossRef] [PubMed]
76. Xu, W.; Kwon, J.-H.; Moon, Y.H.; Kim, Y.B.; Yu, Y.S.; Lee, N.; Choi, K.Y.; Kim, Y.S.; Park, Y.K.; Kim, B.W.; et al. Influence of preoperative transcatheter arterial chemoembolization on gene expression in the HIF-1α pathway in patients with hepatocellular carcinoma. J Cancer Res Clin Oncol 2014, 140, 1507–1515. [Google Scholar] [CrossRef] [PubMed]
77. Huang, M.; Wang, L.; Chen, J.; Bai, M.; Zhou, C.; Liu, S.; Lin, Q. Regulation of COX-2 expression and epithelial-to-mesenchymal transition by hypoxia-inducible factor-1alpha is associated with poor prognosis in hepatocellular carcinoma patients post TACE surgery. Int J Oncol 2016, 48, 2144–2154. [Google Scholar] [CrossRef] [PubMed]
78. Noman, M.Z.; Desantis, G.; Janji, B.; Hasmim, M.; Karray, S.; Dessen, P.; Bronte, V.; Chouaib, S. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 2014, 211, 781–790. [Google Scholar] [CrossRef] [PubMed]
79. Rhee, T.K.; Young, J.Y.; Larson, A.C.; Haines, G.K.; Sato, K.T.; Salem, R.; Mulcahy, M.F.; Kulik, L.M.; Paunesku, T.; Woloschak, G.E.; et al. Effect of transcatheter arterial embolization on levels of hypoxia-inducible factor-1alpha in rabbit VX2 liver tumors. Journal of Vascular and Interventional Radiology : JVIR 2007, 18, 639–645. [Google Scholar] [CrossRef] [PubMed]
80. Greenberger, L.M.; Horak, I.D.; Filpula, D.; Sapra, P.; Westergaard, M.; Frydenlund, H.F.; Albaek, C.; Schrøder, H.; Ørum, H. A RNA antagonist of hypoxia-inducible factor-1alpha, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 2008, 7, 3598–3608. [Google Scholar] [CrossRef]
81. Zhu, H.; Wang, D.-D.; Yuan, T.; Yan, F.-J.; Zeng, C.-M.; Dai, X.-Y.; Chen, Z.-B.; Chen, Y.; Zhou, T.; Fan, G.-H.; et al. Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R-YAP Axis. Cancer Res 2018, 78, 3995–4006. [Google Scholar] [CrossRef]
82. Xu, J.; Zheng, L.; Chen, J.; Sun, Y.; Lin, H.; Jin, R.-A.; Tang, M.; Liang, X.; Cai, X. Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals. Cell Death Dis 2017, 8, e3095. [Google Scholar] [CrossRef] [PubMed]
83. Zhou, Y.; Dong, X.; Xiu, P.; Wang, X.; Yang, J.; Li, L.; Li, Z.; Sun, P.; Shi, X.; Zhong, J. Meloxicam, a Selective COX-2 Inhibitor, Mediates Hypoxia-Inducible Factor- (HIF-) 1α Signaling in Hepatocellular Carcinoma. Oxid Med Cell Longev 2020, 2020, 7079308. [Google Scholar] [CrossRef] [PubMed]
84. Bahrami, A.; Atkin, S.L.; Majeed, M.; Sahebkar, A. Effects of curcumin on hypoxia-inducible factor as a new therapeutic target. Pharmacol Res 2018, 137, 159–169. [Google Scholar] [CrossRef] [PubMed]
85. Su, Q.; Fan, M.; Wang, J.; Ullah, A.; Ghauri, M.A.; Dai, B.; Zhan, Y.; Zhang, D.; Zhang, Y. Sanguinarine inhibits epithelial-mesenchymal transition via targeting HIF-1α/TGF-β feed-forward loop in hepatocellular carcinoma. Cell Death Dis 2019, 10, 939. [Google Scholar] [CrossRef] [PubMed]
86. Li, X.; Tsauo, J.; Geng, C.; Zhao, H.; Lei, X.; Li, X. Ginsenoside Rg3 Decreases NHE1 Expression via Inhibiting EGF-EGFR-ERK1/2-HIF-1 Pathway in Hepatocellular Carcinoma: A Novel Antitumor Mechanism. Am J Chin Med 2018, 46, 1915–1931. [Google Scholar] [CrossRef] [PubMed]
87. Ullah, A.; Ullah, N.; Nawaz, T.; Aziz, T. Molecular Mechanisms of Sanguinarine in Cancer Prevention and Treatment. Anticancer Agents Med Chem 2023, 23, 765–778. [Google Scholar] [CrossRef]
88. Shao, S.; Duan, W.; Xu, Q.; Li, X.; Han, L.; Li, W.; Zhang, D.; Wang, Z.; Lei, J. Curcumin Suppresses Hepatic Stellate Cell-Induced Hepatocarcinoma Angiogenesis and Invasion through Downregulating CTGF. Oxid Med Cell Longev 2019, 2019, 1–12. [Google Scholar] [CrossRef] [PubMed]
89. Li, Y.; Zhao, L.; Li, X.-F. Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy. Front Oncol 2021, 11, 700407. [Google Scholar] [CrossRef] [PubMed]
90. Denny, W.A. The role of hypoxia-activated prodrugs in cancer therapy. Lancet Oncol 2000, 1, 25–29. [Google Scholar] [CrossRef]
91. Cai, T.-Y.; Liu, X.-W.; Zhu, H.; Cao, J.; Zhang, J.; Ding, L.; Lou, J.-S.; He, Q.-J.; Yang, B. Tirapazamine Sensitizes Hepatocellular Carcinoma Cells to Topoisomerase I Inhibitors via Cooperative Modulation of Hypoxia-Inducible Factor-1α. Mol Cancer Ther 2014, 13, 630–642. [Google Scholar] [CrossRef]
92. Tran, N.H.; Foster, N.R.; Mahipal, A.; Byrne, T.; Hubbard, J.; Silva, A.; Mody, K.; Alberts, S.; Borad, M.J. Phase IB study of sorafenib and evofosfamide in patients with advanced hepatocellular and renal cell carcinomas (NCCTG N1135, Alliance). Invest New Drugs 2021, 39, 1072–1080. [Google Scholar] [CrossRef]
93. Schneider, M.A.; Linecker, M.; Fritsch, R.; Muehlematter, U.J.; Stocker, D.; Pestalozzi, B.; Samaras, P.; Jetter, A.; Kron, P.; Petrowsky, H.; et al. Phase Ib dose-escalation study of the hypoxia-modifier Myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors. Nat Commun 2021, 12, 3807. [Google Scholar] [CrossRef] [PubMed]
94. Abbattista, M.R.; Jamieson, S.M.F.; Gu, Y.; Nickel, J.E.; Pullen, S.M.; Patterson, A.V.; Wilson, W.R.; Guise, C.P. Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma. Cancer Biol Ther 2015, 16, 610–622. [Google Scholar] [CrossRef]
95. Vanderborght, B.; De Muynck, K.; Lefere, S.; Geerts, A.; Degroote, H.; Verhelst, X.; Van Vlierberghe, H.; Devisscher, L. Effect of isoform-specific HIF-1α and HIF-2α antisense oligonucleotides on tumorigenesis, inflammation and fibrosis in a hepatocellular carcinoma mouse model. Oncotarget 2020, 11, 4504–4520. [Google Scholar] [CrossRef]
96. Post, D.E.; Sandberg, E.M.; Kyle, M.M.; Devi, N.S.; Brat, D.J.; Xu, Z.; Tighiouart, M.; Van Meir, E.G. Targeted cancer gene therapy using a hypoxia inducible factor dependent oncolytic adenovirus armed with interleukin-4. Cancer Res 2007, 67, 6872–6881. [Google Scholar] [CrossRef] [PubMed]
97. Yousaf, I.; Kaeppler, J.; Frost, S.; Seymour, L.W.; Jacobus, E.J. Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus Infection Coincides with Decreased Vessel Perfusion. Cancers 2020, 12. [Google Scholar] [CrossRef] [PubMed]
98. Solocinski, K.; Padget, M.R.; Fabian, K.P.; Wolfson, B.; Cecchi, F.; Hembrough, T.; Benz, S.C.; Rabizadeh, S.; Soon-Shiong, P.; Schlom, J.; et al. Overcoming hypoxia-induced functional suppression of NK cells. J Immunother Cancer 2020, 8. [Google Scholar] [CrossRef]
99. Wei, M.Q.; Ellem, K.A.O.; Dunn, P.; West, M.J.; Bai, C.X.; Vogelstein, B. Facultative or obligate anaerobic bacteria have the potential for multimodality therapy of solid tumours. Eur J Cancer 2007, 43, 490–496. [Google Scholar] [CrossRef]
100. Hua, H.; Zhu, Y.; Song, Y.-H. Ruscogenin suppressed the hepatocellular carcinoma metastasis via PI3K/Akt/mTOR signaling pathway. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 2018, 101, 115–122. [Google Scholar] [CrossRef]
101. Yang, X.; Yang, C.; Zhang, S.; Geng, H.; Zhu, A.X.; Bernards, R.; Qin, W.; Fan, J.; Wang, C.; Gao, Q. Precision treatment in advanced hepatocellular carcinoma. Cancer Cell 2024, 42, 180–197. [Google Scholar] [CrossRef]
102. Chen, W.; He, C.; Qiao, N.; Guo, Z.; Hu, S.; Song, Y.; Wang, H.; Zhang, Z.; Ke, B.; Sun, X. Dual drugs decorated bacteria irradiate deep hypoxic tumor and arouse strong immune responses. Biomaterials 2022, 286, 121582. [Google Scholar] [CrossRef] [PubMed]
103. Yang, Z.; Zhu, Y.; Dong, Z.; Hao, Y.; Wang, C.; Li, Q.; Wu, Y.; Feng, L.; Liu, Z. Engineering bioluminescent bacteria to boost photodynamic therapy and systemic anti-tumor immunity for synergistic cancer treatment. Biomaterials 2022, 281, 121332. [Google Scholar] [CrossRef]
104. Huang, M.; Yang, L.; Peng, X.; Wei, S.; Fan, Q.; Yang, S.; Li, X.; Li, B.; Jin, H.; Wu, B.; et al. Autonomous glucose metabolic reprogramming of tumour cells under hypoxia: opportunities for targeted therapy. J Exp Clin Cancer Res 2020, 39, 185. [Google Scholar] [CrossRef] [PubMed]
105. Hu, L.; Zeng, Z.; Xia, Q.; Liu, Z.; Feng, X.; Chen, J.; Huang, M.; Chen, L.; Fang, Z.; Liu, Q.; et al. Metformin attenuates hepatoma cell proliferation by decreasing glycolytic flux through the HIF-1α/PFKFB3/PFK1 pathway. Life Sci 2019, 239, 116966. [Google Scholar] [CrossRef] [PubMed]
106. Manchester, L.C.; Coto-Montes, A.; Boga, J.A.; Andersen, L.P.H.; Zhou, Z.; Galano, A.; Vriend, J.; Tan, D.-X.; Reiter, R.J. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res 2015, 59, 403–419. [Google Scholar] [CrossRef] [PubMed]
107. Goradel, N.H.; Asghari, M.H.; Moloudizargari, M.; Negahdari, B.; Haghi-Aminjan, H.; Abdollahi, M. Melatonin as an angiogenesis inhibitor to combat cancer: Mechanistic evidence. Toxicol Appl Pharmacol 2017, 335, 56–63. [Google Scholar] [CrossRef] [PubMed]
108. Choueiri, T.K.; Kaelin, W.G. Targeting the HIF2-VEGF axis in renal cell carcinoma. Nat Med 2020, 26, 1519–1530. [Google Scholar] [CrossRef] [PubMed]
109. Gao, Y.; Xiao, X.; Zhang, C.; Yu, W.; Guo, W.; Zhang, Z.; Li, Z.; Feng, X.; Hao, J.; Zhang, K.; et al. Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-κB/iNOS signaling pathways. J Pineal Res 2017, 62. [Google Scholar] [CrossRef] [PubMed]
110. Sánchez, D.I.; González-Fernández, B.; San-Miguel, B.; de Urbina, J.O.; Crespo, I.; González-Gallego, J.; Tuñón, M.J. Melatonin prevents deregulation of the sphingosine kinase/sphingosine 1-phosphate signaling pathway in a mouse model of diethylnitrosamine-induced hepatocellular carcinoma. J Pineal Res 2017, 62. [Google Scholar] [CrossRef]
111. Yan, J.-J.; Shen, F.; Wang, K.; Wu, M.-C. Patients with advanced primary hepatocellular carcinoma treated by melatonin and transcatheter arterial chemoembolization: a prospective study. Hepatobiliary Pancreat Dis Int 2002, 1, 183–186. [Google Scholar]
112. Chen, L.; Sun, T.; Lv, Y.; Lu, X.; Li, X.; Zhang, H.; Qian, K.; Guo, X.; Sun, B.; Zhang, W.; et al. Efficacy, mechanism, and safety of melatonin-loaded on thermosensitive nanogels for rabbit VX2 tumor embolization: A novel design. J Pineal Res 2023, 75, e12900. [Google Scholar] [CrossRef] [PubMed]
113. Liang, B.; Zheng, C.; Feng, G.; Wu, H.; Wang, Y.; Zhao, H.; Li, X.; Qian, J.; Liang, H. Experimental evaluation of inhibitory effect of 10-hydroxycamptothecin on hypoxia-inducible factor-1α expression and angiogenesis in liver tumors after transcatheter arterial embolization. Journal of Vascular and Interventional Radiology : JVIR 2010, 21, 1565–1572. [Google Scholar] [CrossRef] [PubMed]
114. Dai, F.; Zhang, X.; Shen, W.; Chen, J.; Liu, L.; Gao, G. Liposomal curcumin inhibits hypoxia-induced angiogenesis after transcatheter arterial embolization in VX2 rabbit liver tumors. Onco Targets Ther 2015, 8, 2601–2611. [Google Scholar] [CrossRef] [PubMed]
115. Zhang, X.; Dai, F.; Chen, J.; Xie, X.; Xu, H.; Bai, C.; Qiao, W.; Shen, W. Antitumor effect of curcumin liposome after transcatheter arterial embolization in VX2 rabbits. Cancer Biol Ther 2019, 20, 642–652. [Google Scholar] [CrossRef] [PubMed]
116. Fu, Z.; Xu, Y.-S.; Cai, C.-Q. Ginsenoside Rg3 inhibits pulmonary fibrosis by preventing HIF-1α nuclear localisation. BMC Pulm Med 2021, 21, 70. [Google Scholar] [CrossRef]
117. Yu, Y.; Zhang, C.; Liu, L.; Li, X. Hepatic arterial administration of ginsenoside Rg3 and transcatheter arterial embolization for the treatment of VX2 liver carcinomas. Exp Ther Med 2013, 5, 761–766. [Google Scholar] [CrossRef] [PubMed]
118. Zhou, B.; Yan, Z.; Liu, R.; Shi, P.; Qian, S.; Qu, X.; Zhu, L.; Zhang, W.; Wang, J. Prospective Study of Transcatheter Arterial Chemoembolization (TACE) with Ginsenoside Rg3 versus TACE Alone for the Treatment of Patients with Advanced Hepatocellular Carcinoma. Radiology 2016, 280, 630–639. [Google Scholar] [CrossRef]
119. Duan, X.; Li, H.; Han, X.; Ren, J.; Li, F.; Ju, S.; Wang, M.; Wang, W. Antitumor properties of arsenic trioxide-loaded CalliSpheres^® microspheres by transarterial chemoembolization in VX2 liver tumor rabbits: suppression of tumor growth, angiogenesis, and metastasis and elongation of survival. Am J Transl Res 2020, 12, 5511–5524. [Google Scholar]
120. Wu, T.; Yao, Y.; Sun, R.; Wang, H.; Zhang, J.; Yin, X.; Zhou, Q.; Huangfu, C. Arterial instillation of rapamycin in treatment of rabbit hepatic xenograft tumors and its effects on VEGF, iNOS, HIF-1α, Bcl-2, Bax expression and microvessel density. Sci Prog 2021, 104, 368504211026417. [Google Scholar] [CrossRef]
121. Lei, H.-W.; Huang, B.-R.; Cai, J.; Li, C.-M.; Shang, C.-B.; Liao, Z.-Y.; Wan, Z.-D. CXCR4 antagonist AMD3100 enhances therapeutic efficacy of transcatheter arterial chemoembolization in rats with hepatocellular carcinoma. Kaohsiung J Med Sci 2022, 38, 781–789. [Google Scholar] [CrossRef]
122. Qu, K.; Yan, Z.; Wu, Y.; Chen, Y.; Qu, P.; Xu, X.; Yuan, P.; Huang, X.; Xing, J.; Zhang, H.; et al. Transarterial chemoembolization aggravated peritumoral fibrosis via hypoxia-inducible factor-1α dependent pathway in hepatocellular carcinoma. J Gastroenterol Hepatol 2015, 30, 925–932. [Google Scholar] [CrossRef] [PubMed]
123. Murugesan, T.; Rajajeyabalachandran, G.; Kumar, S.; Nagaraju, S.; Jegatheesan, S.K. Targeting HIF-2α as therapy for advanced cancers. Drug Discov Today 2018, 23, 1444–1451. [Google Scholar] [CrossRef]
124. Ma, L.; Li, G.; Zhu, H.; Dong, X.; Zhao, D.; Jiang, X.; Li, J.; Qiao, H.; Ni, S.; Sun, X. 2-Methoxyestradiol synergizes with sorafenib to suppress hepatocellular carcinoma by simultaneously dysregulating hypoxia-inducible factor-1 and -2. Cancer Lett 2014, 355. [Google Scholar] [CrossRef] [PubMed]
125. Chen, M.; Shu, G.; Lv, X.; Xu, X.; Lu, C.; Qiao, E.; Fang, S.; Shen, L.; Zhang, N.; Wang, J.; et al. HIF-2α-targeted interventional chemoembolization multifunctional microspheres for effective elimination of hepatocellular carcinoma. Biomaterials 2022, 284, 121512. [Google Scholar] [CrossRef] [PubMed]
126. Gandara, D.R.; Lara, P.N.; Goldberg, Z.; Le, Q.T.; Mack, P.C.; Lau, D.H.M.; Gumerlock, P.H. Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia. Semin Oncol 2002, 29, 102–109. [Google Scholar] [CrossRef]
127. Sonoda, A.; Nitta, N.; Ohta, S.; Nitta-Seko, A.; Nagatani, Y.; Takahashi, M.; Murata, K. Enhanced antitumor effect of tirapazamine delivered intraperitoneally to VX2 liver tumor-bearing rabbits subjected to transarterial hepatic embolization. Cardiovascular and Interventional Radiology 2011, 34, 1272–1277. [Google Scholar] [CrossRef] [PubMed]
128. Lin, W.-H.; Yeh, S.-H.; Yeh, K.-H.; Chen, K.-W.; Cheng, Y.-W.; Su, T.-H.; Jao, P.; Ni, L.-C.; Chen, P.-J.; Chen, D.-S. Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice. Proc Natl Acad Sci U S A 2016, 113, 11937–11942. [Google Scholar] [CrossRef] [PubMed]
129. Liu, C.-H.; Kuo, S.-M.; Gao, H.-W.; Hsu, Y.-J. A rat toxicological study of intra-arterial injection of Tirapazamine, a hypoxia-activating Cancer therapeutic agent, followed by hepatic artery ligation. Invest New Drugs 2021, 39, 747–755. [Google Scholar] [CrossRef] [PubMed]
130. Liu, C.-H.; Peng, C.-M.; Hwang, J.-I.; Liang, P.-C.; Chen, P.-J.; Abi-Jaoudeh, N.; Giiang, L.-H.; Tyan, Y.-S. Phase I Dose-Escalation Study of Tirapazamine Chemoembolization for Unresectable Early- and Intermediate-Stage Hepatocellular Carcinoma. Journal of Vascular and Interventional Radiology : JVIR. [CrossRef]
131. Abi-Jaoudeh, N.; Dayyani, F.; Chen, P.J.; Fernando, D.; Fidelman, N.; Javan, H.; Liang, P.C.; Hwang, J.I.; Imagawa, D.K. Phase I Trial on Arterial Embolization with Hypoxia Activated Tirapazamine for Unresectable Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021, 8, 421–434. [Google Scholar] [CrossRef]
132. Duan, J.-X.; Jiao, H.; Kaizerman, J.; Stanton, T.; Evans, J.W.; Lan, L.; Lorente, G.; Banica, M.; Jung, D.; Wang, J.; et al. Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs. J Med Chem 2008, 51, 2412–2420. [Google Scholar] [CrossRef]
133. Hu, J.; Handisides, D.R.; Van Valckenborgh, E.; De Raeve, H.; Menu, E.; Vande Broek, I.; Liu, Q.; Sun, J.D.; Van Camp, B.; Hart, C.P.; et al. Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug. Blood 2010, 116, 1524–1527. [Google Scholar] [CrossRef]
134. Liu, Q.; Sun, J.D.; Wang, J.; Ahluwalia, D.; Baker, A.F.; Cranmer, L.D.; Ferraro, D.; Wang, Y.; Duan, J.-X.; Ammons, W.S.; et al. TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules. Cancer Chemother Pharmacol 2012, 69, 1487–1498. [Google Scholar] [CrossRef]
135. Sun, J.D.; Liu, Q.; Wang, J.; Ahluwalia, D.; Ferraro, D.; Wang, Y.; Duan, J.-X.; Ammons, W.S.; Curd, J.G.; Matteucci, M.D.; et al. Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer. Clin Cancer Res 2012, 18, 758–770. [Google Scholar] [CrossRef]
136. Portwood, S.; Lal, D.; Hsu, Y.-C.; Vargas, R.; Johnson, M.K.; Wetzler, M.; Hart, C.P.; Wang, E.S. Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models. Clin Cancer Res 2013, 19, 6506–6519. [Google Scholar] [CrossRef]
137. Weiss, G.J.; Infante, J.R.; Chiorean, E.G.; Borad, M.J.; Bendell, J.C.; Molina, J.R.; Tibes, R.; Ramanathan, R.K.; Lewandowski, K.; Jones, S.F.; et al. Phase 1 study of the safety, tolerability, and pharmacokinetics of TH-302, a hypoxia-activated prodrug, in patients with advanced solid malignancies. Clin Cancer Res 2011, 17, 2997–3004. [Google Scholar] [CrossRef] [PubMed]
138. Duran, R.; Mirpour, S.; Pekurovsky, V.; Ganapathy-Kanniappan, S.; Brayton, C.F.; Cornish, T.C.; Gorodetski, B.; Reyes, J.; Chapiro, J.; Schernthaner, R.E.; et al. Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer. Clin Cancer Res 2017, 23, 536–548. [Google Scholar] [CrossRef] [PubMed]
139. Ma, P.; Chen, J.; Qu, H.; Li, Y.; Li, X.; Tang, X.; Song, Z.; Xin, H.; Zhang, J.; Nai, J.; et al. Hypoxic targeting and activating TH-302 loaded transcatheter arterial embolization microsphere. Drug Deliv 2020, 27, 1412–1424. [Google Scholar] [CrossRef] [PubMed]
140. Hannon, G.J. RNA interference. Nature 2002, 418, 244–251. [Google Scholar] [CrossRef]
141. Chen, C.; Wang, J.; Liu, R.; Qian, S. RNA interference of hypoxia-inducible factor-1 alpha improves the effects of transcatheter arterial embolization in rat liver tumors. Tumour Biol 2012, 33, 1095–1103. [Google Scholar] [CrossRef]
142. Chen, C.-S.; Zhao, Q.; Qian, S.; Li, H.-L.; Guo, C.-Y.; Zhang, W.; Yan, Z.-P.; Liu, R.; Wang, J.-H. Ultrasound-guided RNA interference targeting HIF-1 alpha improves the effects of transarterial chemoembolization in rat liver tumors. Onco Targets Ther 2015, 8, 3539–3548. [Google Scholar] [CrossRef]
143. Ni, J.-Y.; Xu, L.-F.; Wang, W.-D.; Huang, Q.-S.; Sun, H.-L.; Chen, Y.-T. Transarterial embolization combined with RNA interference targeting hypoxia-inducible factor-1α for hepatocellular carcinoma: a preliminary study of rat model. J Cancer Res Clin Oncol 2017, 143, 199–207. [Google Scholar] [CrossRef] [PubMed]
144. Guo, C.; Wang, C.; Zhang, J.; Chen, X. Treatment for Liver Tumor Using Combined Transarterial Embolization and Interaarterial Transfecting HIF-1α shRNA in a Rabbit VX2 Model. Onco Targets Ther 2020, 13, 8511–8519. [Google Scholar] [CrossRef] [PubMed]
145. Liu, J.; Cao, G.; Liu, J.; Zhao, X.; Cao, H. Long non-coding RNA MIAT knockdown potentiates the therapeutic effect of transcatheter arterial embolization in liver cancer by regulating the miR-203a/HIF-1α axis. Oncology Reports 2020, 44, 722–734. [Google Scholar] [CrossRef] [PubMed]
146. Liu, Q.; Fan, D.; Adah, D.; Wu, Z.; Liu, R.; Yan, Q.-T.; Zhang, Y.; Du, Z.-Y.; Wang, D.; Li, Y.; et al. CRISPR/Cas9-mediated hypoxia inducible factor-1α knockout enhances the antitumor effect of transarterial embolization in hepatocellular carcinoma. Oncology Reports 2018, 40, 2547–2557. [Google Scholar] [CrossRef] [PubMed]
147. Altomonte, J.; Braren, R.; Schulz, S.; Marozin, S.; Rummeny, E.J.; Schmid, R.M.; Ebert, O. Synergistic antitumor effects of transarterial viroembolization for multifocal hepatocellular carcinoma in rats. Hepatology 2008, 48, 1864–1873. [Google Scholar] [CrossRef] [PubMed]
148. Sun, X.; Jiang, H.; Jiang, X.; Tan, H.; Meng, Q.; Sun, B.; Xu, R.; Krissansen, G.W. Antisense hypoxia-inducible factor-1alpha augments transcatheter arterial embolization in the treatment of hepatocellular carcinomas in rats. Hum Gene Ther 2009, 20, 314–324. [Google Scholar] [CrossRef] [PubMed]
149. Zhang, H.; Xiong, F.; Qian, K.; Liu, Y.; Liang, B.; Xiong, B.; Yang, F.; Zheng, C. Transcatheter arterial embolization combined with hypoxia-replicative oncolytic adenovirus perfusion enhances the therapeutic effect of hepatic carcinoma. Cancer Manag Res 2019, 11, 981–996. [Google Scholar] [CrossRef] [PubMed]
150. Cao, Y.; Xiong, F.; Kan, X.; Guo, X.; Ouyang, T.; Wang, R.; Yang, J.; Cai, L.; Liu, B.; Liang, B.; et al. Transarterial viroembolization improves the therapeutic efficacy of immune-excluded liver cancer: Three birds with one stone. Pharmacol Res 2023, 187, 106581. [Google Scholar] [CrossRef]
151. Geschwind, J.-F.H.; Ko, Y.H.; Torbenson, M.S.; Magee, C.; Pedersen, P.L. Novel therapy for liver cancer: direct intraarterial injection of a potent inhibitor of ATP production. Cancer Res 2002, 62, 3909–3913. [Google Scholar] [PubMed]
152. Vossen, J.A.; Buijs, M.; Syed, L.; Kutiyanwala, F.; Kutiyanwala, M.; Geschwind, J.-F.H.; Vali, M. Development of a new orthotopic animal model of metastatic liver cancer in the rabbit VX2 model: effect on metastases after partial hepatectomy, intra-arterial treatment with 3-bromopyruvate and chemoembolization. Clin Exp Metastasis 2008, 25, 811–817. [Google Scholar] [CrossRef]
153. Wilkins, L.R.; Brautigan, D.L.; Wu, H.; Yarmohammadi, H.; Kubicka, E.; Serbulea, V.; Leitinger, N.; Liu, W.; Haaga, J.R. Cinnamic Acid Derivatives Enhance the Efficacy of Transarterial Embolization in a Rat Model of Hepatocellular Carcinoma. Cardiovascular and Interventional Radiology 2017, 40, 430–437. [Google Scholar] [CrossRef] [PubMed]
154. Yarmohammadi, H.; Wilkins, L.R.; Erinjeri, J.P.; Novak, R.D.; Exner, A.A.; Wu, H.; Petre, E.N.; Boas, E.; Ziv, E.; Haaga, J.R. Efficiency of combined blocking of aerobic and glycolytic metabolism pathways in treatment of N1-S1 hepatocellular carcinoma in a rat model. J Cancer Res Ther 2017, 13, 533–537. [Google Scholar] [CrossRef] [PubMed]
155. Martin, S.P.; Fako, V.; Dang, H.; Dominguez, D.A.; Khatib, S.; Ma, L.; Wang, H.; Zheng, W.; Wang, X.W. PKM2 inhibition may reverse therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma. J Exp Clin Cancer Res 2020, 39, 99. [Google Scholar] [CrossRef]
156. Luo, Y.; Yang, Y.; Ye, M.; Zuo, J. Targeting metabolic reprogramming promotes the efficacy of transarterial chemoembolization in the rabbit VX2 liver tumor model. Oncol Lett 2024, 27, 111. [Google Scholar] [CrossRef] [PubMed]
157. Feng, J.; Zhou, J.; Wu, Y.; Shen, H.-M.; Peng, T.; Lu, G.-D. Targeting mitophagy as a novel therapeutic approach in liver cancer. Autophagy 2023, 19, 2164–2165. [Google Scholar] [CrossRef] [PubMed]
158. Lin, X.-H.; Qiu, B.-Q.; Ma, M.; Zhang, R.; Hsu, S.-J.; Liu, H.-H.; Chen, J.; Gao, D.-M.; Cui, J.-F.; Ren, Z.-G.; et al. Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia. Oncogenesis 2020, 9, 67. [Google Scholar] [CrossRef] [PubMed]
159. Zhong, C.; Niu, Y.; Liu, W.; Yuan, Y.; Li, K.; Shi, Y.; Qiu, Z.; Li, K.; Lin, Z.; Huang, Z.; et al. S100A9 Derived from Chemoembolization-Induced Hypoxia Governs Mitochondrial Function in Hepatocellular Carcinoma Progression. Adv Sci (Weinh) 2022, 9, e2202206. [Google Scholar] [CrossRef]
160. Zhou, J.; Feng, J.; Wu, Y.; Dai, H.-Q.; Zhu, G.-Z.; Chen, P.-H.; Wang, L.-M.; Lu, G.; Liao, X.-W.; Lu, P.-Z.; et al. Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagy. Exp Mol Med 2022, 54, 2007–2021. [Google Scholar] [CrossRef]