Hypoxia Inducible Factor Pathway Inhibitors as Anticancer Therapeutics

Burroughs, Sarah; Kaluz, Štefan; Wang, Danzhu; Wang, Ke; Meir, Erwin G. Van; Wang, Binghe

doi:10.4155/fmc.13.17

Cited by 130 publications

(116 citation statements)

References 203 publications

(169 reference statements)

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“…В литературе активно обсуждается проблема целенаправленного ингибирования активности HIF-факторов (в первую очередь, HIF-1) при комплексном лечении онкологических заболеваний [80]. На сегодняшний день ни один из потенциальных анти-HIF-1 препаратов не одобрен для клинического применения.…”

Section: транскрипционные факторы: фактор индуцированный гипоксией-1unclassified

“…На сегодняшний день ни один из потенциальных анти-HIF-1 препаратов не одобрен для клинического применения. Многими исследователями подвергается сомнению сама возможность подобрать действительно эффективные и специфичные ингибиторы HIF-1 [80]. В основном, эти сомнения связаны с представлением о том, что транскрипционные факторы, каковым является HIF-1, принципиально не могут выступать в качестве молекулярных мишеней для искусственно полученных химических агентов.…”

Section: транскрипционные факторы: фактор индуцированный гипоксией-1unclassified

“…Во-первых, HIF-1 интегрирует многочисленные (в том числе, функционально противоположные) сигнальные каскады, из-за чего практически невозможно предсказать конечный результат ингибирования его активности. Во-вторых, пока считается маловероятной разработка химических соединений, блокирующих многочисленные белок-белковые взаимодействия, составляющие суть трансактивирующего действия HIF-1 [80]. Некоторые из применяемых сегодня анти-ангиогенных таргетных препаратов косвенно влияют на экспрессию/активность HIF-1, так как действуют на общие регуляторные компоненты сигнальных путей клетки (например, mTOR-ингибиторы).…”

Section: транскрипционные факторы: фактор индуцированный гипоксией-1unclassified

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Remodeling of angiogenesis and lymphangiogenesis in cervical cancer development

et al. 2015

BIOMED KHIM

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Ability to stimulate angiogenesis/lymphangiogenesis is recognized as an inherent feature of cancer cells providing necessary conditions for their growth and dissemination. “Angiogenic switch” is one of the earliest consequences of malignant transformation that encompasses a great number of genes and triggers a complex set of signaling cascades in endothelial cells. The processes of tumor microvasculature development are closely connected to the steps of carcinogenesis (from benign lesions to invasive forms) and occur through multiple deviations from the norm. Analysis of expression of proangiogenic factors at successive steps of cervical cancer development (intraepithelial neoplasia, cancer in situ, microinvasive, and invasive cancer) enables to reconstruct the regulatory mechanisms of (lymph-)angiogenesis and to discriminate the most important components. This review presents detailed analysis of literature data on expression of the key regulators of angiogenesis in cervical intraepithelial neoplasia and cervical cancer. Their possible involvement in molecular mechanisms of neoplastic transformation of epithelial cells, as well as invasion and tumor metastasis is discussed. Correlation between expression of proangiogenic molecular factors and various clinicopathological parameters is considered, the potential of their use in molecular diagnostics and targeted therapy of cervical cancer is reviewed. Particular attention is paid to relatively poorly studied regulators of lymphangiogenesis and “non-VEGF dependent”, or alternative, angiogenic pathways that constitute the prospect of future research in the field.

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Section: транскрипционные факторы: фактор индуцированный гипоксией-1unclassified

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Remodeling of angiogenesis and lymphangiogenesis in cervical cancer development

et al. 2015

BIOMED KHIM

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“…Hypoxia activates the hypoxia inducible factor (HIF) pathway and upregulates HIF-1α, which mediates multiple biological effects of hypoxia in tissues and increases resistance against chemotherapy and radiation. [89] Several small molecule inhibitors of the HIF pathway have been pursued in clinical trials, although only a few of them were successful. Bortezomib (Velcade ® , PS-341) was approved by the FDA in 2003 for use against multiple myeloma, followed by Temsirolimus (Torisel ® , CCI-779), approved in 2007 for use against renal cell carcinoma.…”

Section: Targeting the Tumor Microenvironmentmentioning

confidence: 99%

“…The majority of the other drugs --including Perifosine, 2-methoxyestradiol, Echinomycin, Geldanamycin --were terminated in either phase I or II trials when they failed to show significant advantages. [89] Lastly, targeting tumor vasculature is another way to disrupt the CSC niche. Several agents blocking the activity of vascular endothelial growth factor, which drives the migration of endothelial cells and stimulates angiogenesis, are being tested in initial phases of clinical therapy with moderate success.…”

Section: Targeting the Tumor Microenvironmentmentioning

confidence: 99%

Therapeutic strategies for targeting cancer stem cells

Kim¹,

Siegler²,

Siriwon³

et al. 2016

JCMT

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The therapeutic limitations of conventional chemotherapeutic drugs present a challenge for cancer therapy; these shortcomings are largely attributed to the ability of cancer cells to repopulate and metastasize after initial therapies. Compelling evidence suggests that cancer stem cells (CSCs) have a crucial impact in current shortcomings of cancer therapy because they are largely responsible for tumor initiation, relapse, metastasis, and chemo-resistance. Thus, a better understanding of the properties and mechanisms underlying CSC resistance to treatments is necessary to improve patient outcomes and survival rates. In this review, the authors characterize and compare different CSC-specific biomarkers that are present in various types of tumors. We further discuss multiple targeting approaches currently in preclinical or clinical testing that show great potential for targeting CSCs. This review discusses numerous strategies to eliminate CSCs by targeting surface biomarkers, regulating CSC-associated oncogenes and signaling pathways, inhibiting drug-efflux pumps involved in drug resistance, modulating the tumor microenvironment and immune system, and applying drug combination therapy using nanomedicine.

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Antitumor effects of low‐dose tipifarnib on the mTOR signaling pathway and reactive oxygen species production in HIF‐1α‐expressing gastric cancer cells

et al. 2021

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Farnesyltransferase inhibitors (FTIs) suppress tumor aggressiveness in several malignancies by inhibiting Ras signaling. However, treatment of cells with a low dose of the FTI tipifarnib suppresses the expression of hypoxia‐inducible factor‐1α (HIF‐1α) and results in antitumor effects without inhibiting the Ras pathway. Although we previously reported that elevated HIF‐1α expression is associated with an aggressive phenotype in gastric cancer (GC), little is known about the antitumor effects of FTIs on GC. In this study, we examined the relationship between the antitumor effects of low‐dose tipifarnib and HIF‐1α expression in GC cells. Under normoxic conditions, HIF‐1α was expressed only in MKN45 and KATOIII cells. The inhibitory effect of tipifarnib on HIF‐1α was observed in HIF‐1α‐positive cells. Low‐dose tipifarnib had antitumor effects only on HIF‐1α‐positive cells both in vitro and in vivo . Furthermore, low‐dose tipifarnib inactivated ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) signaling and decreased intracellular reactive oxygen species (ROS) levels in HIF‐1α‐positive GC cells. Our results that the antitumor effects of low‐dose tipifarnib are at least partially mediated through suppression of mTOR signaling and HIF‐1α expression via inhibition of Rheb farnesylation and reduction in ROS levels. These findings suggest that low‐dose tipifarnib may be capable of exerting an antitumor effect that is dependent on HIF‐1α expression in GC cells. Tipifarnib may have potential as a novel therapeutic agent for HIF‐1α‐expressing GC exhibiting an aggressive phenotype.

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Hypoxia Inducible Factor Pathway Inhibitors as Anticancer Therapeutics

Cited by 130 publications

References 203 publications

Remodeling of angiogenesis and lymphangiogenesis in cervical cancer development

Remodeling of angiogenesis and lymphangiogenesis in cervical cancer development

Therapeutic strategies for targeting cancer stem cells

Antitumor effects of low‐dose tipifarnib on the mTOR signaling pathway and reactive oxygen species production in HIF‐1α‐expressing gastric cancer cells

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