Page 52 - Read Online

Page 4 of 8 Lin et al. Hepatoma Res 2018;4:26 I http://dx.doi.org/10.20517/2394-5079.2018.27

THERAPEUTIC STRATEGIES TARGETING-HYPOXIA FOR HCC TREATMENT
[45]
Sorafenib is the only effective first-line drug for advanced HCC . However, hypoxia-induced chemoresistance
[43]
to sorafenib leads to treatment failure . Hypoxia also confers resistance to various anticancer drugs in HCC
[6]
cells, including etoposide, sorafenib, SN38, cisplatin and doxorubicin . As hypoxia induces tumor malignant
[14]
transformation and plays an important role in resistance to radiotherapy and chemotherapy , target-hypoxia
therapy is reasonable in HCC treatment. There are several approaches to target hypoxic microenvironment.
One approach is to design hypoxia-activated bioreductive pro-drugs which would be activated by enzymatic
reduction in hypoxic tissue; the other one is to target key molecules specifically activated in hypoxic cells,
[46]
such as the most studied HIFs inhibitors. In addition, emerging new strategies such as oxygen supplement
[47]
and vessel normalization were also developed to target the hypoxic cancers.

Bioreductive prodrugs
Bioreductive prodrugs generally share a common mechanism of activation. They are activated by enzymatic
[48]
reduction in hypoxic tissue to form cytotoxins, resulting in hypoxia-selective cell killing .
[48]
OXY111A is a synthetic allosteric effector of hemoglobin-4 and promotes normoxia in hypoxic tumors .
OXY111A has been tested in several cancer animal models, showing beneficial outcomes and low side effect
[6]
[49]
profiles . It is also shown to prevent HIF1α stabilization as well as VEGF production . Tirapazamine
(TPZ; SR4233) belongs to the aromatic N-oxide family and has been extensively evaluated. TPZ is reported
to potentiate the antitumor efficacy of many anticancer drugs [50-54] , becoming a promising compound
in combination-therapy. In addition, TPZ can also sensitize HCC cells to topoisomerase I inhibitors via
[54]
[55]
cooperative modulation of HIF1α . As a novel hypoxia-activated prodrug, Q6 arrests tumor growth in
vivo through dual hypoxia-targeted regulatory mechanisms. Q6 exhibits potent antiproliferative efficacy and
induces apoptosis in HCC under hypoxic. Besides, Q6 can induce attenuation of HIF1α expression through
autophagy-dependent degradation pathway as well. Recent study suggests that Q6 induces G2-M arrest and
[56]
apoptosis via poisoning topoisomerase II . Thus Q6 shows a more potent anti-proliferative effect than TPZ.
Drugs targeting hypoxia related molecules
As a curcumin analog, diphenyl difluoroketone (EF24) is an effective and promising anticancer compound.
EF24 enhance the antitumor effects of sorafenib and overcomes sorafenib resistance through VHL (Von
[6]
Hippel-Lindau tumor suppressor)-dependent HIF1α degradation and NF-κB inactivation . Generally, EF24
exerts its effects by inhibition of proliferation and induction of apoptosis. It is reported that EF24 induces
G2/M arrest and apoptosis by increasing phosphatase and tensin homologue expression (PTEN) in ovarian
[57]
cancer cells . Recently, EF24 has been shown to suppress invasion and migration of HCC cells in vitro via
[58]
inhibiting the phosphorylation of src . A series of compounds targeting hypoxia HCC are on clinical trials,
such as RO7070179 and EZN-2968, both of which are antisense oligonucleotide inhibitors of HIF1α [31,59] .
Other compounds like Bufalin (target inhibition of PI3K-AKT-mTOR activity), ENMD-1198 (a microtubule
destabilizing agent) and Metformin (an established antidiabetic drug) are involved in the suppression HIF1α
expression [6,60] .

The other treatments
Hyperbaric oxygen (HBO) treatment can enhance the amount of dissolved oxygen in the plasma and
increase O delivery to the tissue oxygen, so it can be used to overcome hypoxia. Both recent and previous
2
research studies have shown that HBO can be inhibitory and reduce cancer growth in some cancer
[46]
[61]
types . Granowitz et al. show that HBO can inhibit benign and malignant human mammary epithelial
[47]
cell proliferation. In another study, Cheng et al. engineered VNP20009 to express histidine-proline-
rich glycoprotein (HPRG) under the control of a hypoxia-induced NirB promoter. HPRG has potent
antiangiogenic and tumor vessel normalization properties. Attenuated Salmonella Typhimurium strain
VNP20009 preferentially accumulates and replicates in hypoxic tumor regions. They found that VNP20009-