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Gene & Protein in Disease Opportunities and challenges of HIF-1 in cancer

is considered a double-edged sword. Some reports indicate 3.1.1. Cisplatin
that HAF-mediated degradation of HIF-1α can limit tumor The efficacy of cisplatin, one of the most well-known
growth. However, the increased ratio of HIF-2α to HIF-1α, small molecules used against neoplasms, appears to be
along with the upregulation of HIF-2α by HAF, leads to influenced by hypoxic conditions. In fact, the effectiveness
significantly less favorable outcomes for the patient. These of cisplatin was hindered under hypoxic conditions,
adverse outcomes are due to enhanced migration and particularly when investigated in HepG2/DDP-resistant
invasion through the activation of different sets of genes, cells compared to HepG2. New drug delivery systems for
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as demonstrated in T24 cells. Consequently, an expanded cisplatin are being investigated and developed to address
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stem cell population, enhanced tumor development and issues such as limited access to the tumor site and the
invasion, increased progression, and morphological and elevated production of ROS associated with the action of
biochemical changes that favor proliferation are expected. this molecule and other obstacles. 87,91
Complimenting these effects is the activation of the
NF-κΒ pathway by interfering with the degradation of 3.1.2. Docetaxel
the IκΒ molecule, which inhibits the NF-κΒ, as well as the Docetaxel is an interesting case as it can limit the expression
induction of VEGF transcription. 83
and accumulation of HIF-1a, resulting in improved clinical
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3. Challenges and limitations of HIF-1 outcomes. In addition, due to its effectiveness on cancer
integration in clinical practice cells even under hypoxic conditions, docetaxel is used as
an alternative to paclitaxel when the latter demonstrates
The hypoxic conditions of the TME increase the potency of no significant effect. Combining docetaxel therapy with
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the neoplasm by rendering several therapeutic approaches nitroglycerin to increase blood flow to the tumor site
ineffective and promoting the survival of the fittest and is controversial, as there are reports with contradicting
most aggressive cells in the tumor population. Granted results and suggestions, although positive outcomes
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the significance of HIF-1 in the survivability of cancer slightly outnumber negative ones. 94-96 HIF-1 activity may
cells in the hypoxic TME and its multifactorial function, also reduce the effectiveness of docetaxel, as observed in
several therapeutic approaches involving the dimer have the study by Li et al. on triple-negative breast cancer.
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been investigated and implemented. These interventions
include the use of substances that regulate the HIF-1 3.1.3. Doxorubicin
activity, such as flavonoids, and molecules that act as A bilateral relationship between doxorubicin and HIF-1
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inhibitors at various stages of the protein’s lifecycle. These has been observed, with HIF-1 inducing resistance to
stages include mRNA expression, protein translation, doxorubicin, which, in turn, promotes autophagy under
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protein degradation, DNA binding, and transcriptional hypoxic conditions. In addition, doxorubicin, when
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activity. 86 Nov el therapies, such as gene therapy, have also assessed in vitro and in vivo through animal models,
been explored. It is evident that HIF-1 plays a significant was found to inhibit the expression of HIF-1 and related
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role in situations where cancer becomes more aggressive genes. However, significant cardiovascular damage,
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and clinically challenging. The impact is observed across one of the most prevalent side effects of doxorubicin,
the therapeutic spectrum, as indicated by elevated HIF-1α should be taken into consideration. To combat the
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serum levels in a study from Brazil. It shall be noted that effects of HIF-1, coencapsulation with inhibitors has been
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a significant majority of the supporting results are derived suggested. 102
from in vivo and in vitro studies.
3.1.4. Gemcitabine
3.1. Chemotherapy
Acquired resistance to gemcitabine is induced through
Beyond radioresistance, HIF-1 has been established as a increased catalase presence induced through the HIF-1/
trigger for pathways involved in the resistance of cancer ABCB6 pathway, resulting in decreased levels of ROS.
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cells to chemotherapeutic agents. This etiology is related to Hypoxic conditions have also been reported to be
the mechanism of radioresistance, as HIF-1 protects cancer related to higher chemoresistance and metastatic ability
cells from damage caused by these agents. In addition, the in cholangiocarcinoma, and the inhibition of HIF-1
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relatively limited blood flow, which results in hypoxia and increases the effectiveness of therapy for PDACs.
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thereby initiates the action of the dimer, poses a challenge However, another study indicates that hypoxia does not
to the efficient and effective delivery of chemotherapeutic influence the cytotoxic and radio-sensitizing effect of
molecules. The following are examples of the effects of gemcitabine and its metabolites. Novel drug delivery
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HIF-1 on the action of some of the most widely used small solutions, such as the use of vectors, can assist in more
oncotherapeutic molecules. targeted and effective treatment using gemcitabine. 107

Volume 3 Issue 2 (2024) 9 doi: 10.36922/gpd.3431