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

3.1.5. Chemodynamic therapy its effectiveness is largely influenced by the capabilities

Chemodynamic therapy relies on hydrogen peroxide for and limitations of the immune response. A characteristic
the production of ROS, which induces oxidative stress example is glioblastoma, which presents challenges due
and cancer cell death. HIF-1 has a protective effect to the complexity of its environment, limited access, and
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against radicals through the expression of GSH, which, heterogeneity.
in turn, inhibits oxidation and the production of ROS. 3.3.1. TME
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In chemodynamic therapy, catalytic molecules can be
combined with anti-HIF factors in a common carrier, such The TME is immunosuppressive and, in general, hostile
as liposomes or other delivery systems. 108-110 toward somatic and immune cells, primarily due to its
hypoxic state driven by HIF-1. Therefore, interference
3.2. Radiation therapy with HIF-1 formation and function can make the tumor
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As mentioned earlier, HIF-1 can be activated by methods more susceptible to immune system attacks. An effective
under the umbrella of radiation therapy due to the strategy may involve the oxygenation of the tumor to
generation of ROS and concurrent vascular damage. These counteract the effects of the dimer, thus enhancing immune
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conditions physiologically mimic a state of hypoxia, thus response. In addition, T-cells are disadvantaged in
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activating HIF-1α and conferring new properties to the hypoxic conditions due to metabolic stress, and acidosis
neoplastic cells. For instance, acquired radioresistance reduces the formation and secretion of interferon-γ and
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of cancer cells is linked to HIF-1-induced hypoxia, tumor necrosis factor-α. 109
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which leads to limited production of ROS and DNA 3.3.2. Checkpoint molecules
damage that can be easily countered by the oxidation of
free sulfhydryl groups on biomolecules such as proteins. HIF-1 promotes the expression of immunosuppressive
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The effects of the dimer are evident in various in vitro factors and immune checkpoint molecules such as
studies. Experiments conducted on the MS5 cell line PD-L1, further dampening the immune response and
of mouse mesenchymal stromal cells cultured under reducing the chance of success for the immunotherapeutic
hypoxic conditions have demonstrated that these cells interventions. 126,127 The impact of this immunosuppressive
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have increased genetic stability and, thus, survivability mechanism is evident in the results of Bailey et al.,
when exposed to ionizing radiation. In terms of in which reported that anti-CTLA-4 therapy is optimized
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vivo studies, relevant neoplasms include prostate and when combined with anti-HIF-1 therapy, yielding
cervical cancer, glioblastoma, squamous cell carcinoma, results comparable to those of PD-1/PD-L1 coupling in
and osteosarcoma. It is noted that post-radiation rodent models. Therefore, the optimal strategy would
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exposure can help prostate cancer cells evade apoptosis be to couple PD-L1 inhibitors with anti-HIF-1 factors.
and maintain stemness, as observed in squamous cell HIF-1 also promotes the expression of CD47, human
carcinoma cells. 116,117 HIF-1 plays a crucial role in the leukocyte antigen-G checkpoint molecule, and V-domain
progression of glioblastoma along with radioresistance due immunoglobin, all of which enhance the immune
to lactate accumulation. Osteosarcoma is particularly evasive characteristics of neoplastic cells in a hypoxic
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interesting because, in addition to the mechanisms environment. 129-131 In addition, two HIF-1 subunit
mentioned above, hypoxia-induced autophagy contributes inhibitors have recently been approved by the United States
to its high potency and radioresistance. Overcoming Food and Drug Administration: daprodustat (Jesduvroq,
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radioresistance is a promising venture, as several molecules GSK), approved in 2023 for treating anemia in adults with
have been reported to increase radiosensitivity by targeting chronic kidney disease on dialysis, 132-134 and belzutifan
HIF-1. For instance, Guo et al. observed that baicalein, (Welireg, Merck), approved in 2021 for adult patients with
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among other compounds, intercepts pathways that lower VHL disease requiring therapy for associated renal cell
radioresistance in KYSE150 squamous cell carcinoma cell carcinoma, central nervous system hemangioblastomas,
lines. Another promising finding is the significant damage or pancreatic neuroendocrine tumors that do not require
observed in HeLa cervical cancer cell lines when placed immediate surgery. 135,136
in a low-oxygen, low-glucose environment, implying lower
radioresistance. 121 3.3.3. Immune cell interaction and cytotoxic activity
In addition to the expression of PD-L1 on dendritic cells,
3.3. Immunotherapy which inhibits T-cells, HF-1 also increases adenosine levels
Immunotherapy is a broad term encompassing some of in the tumor, which negatively affect CD8 T lymphocytes,
the most recent and effective strategies against cancer. As and the resulting lactate accumulation from the hypoxic
this therapeutic approach is based on the immune system, conditions promotes M2 macrophage polarization,
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Volume 3 Issue 2 (2024) 10 doi: 10.36922/gpd.3431