HIF-1α inhibitor PX-478 for cancer therapy and other fields

Research Article
Open access

HIF-1α inhibitor PX-478 for cancer therapy and other fields

Lingquan Zhang 1*
  • 1 The Chinese University of Hong Kong (Shen Zhen)    
  • *corresponding author 120090589@link.edu.cn
Published on 20 December 2023 | https://doi.org/10.54254/2753-8818/21/20230891
TNS Vol.21
ISSN (Print): 2753-8826
ISSN (Online): 2753-8818
ISBN (Print): 978-1-83558-215-2
ISBN (Online): 978-1-83558-216-9

Abstract

Hypoxia-inducible factor 1-alpha (HIF-1α) is a crucial transcription factor for tumor growth and progression. PX-478, a small molecule HIF-1α inhibitor, has been extensively studied for its potential as an anti-cancer agent in preclinical studies. This paper provides an overview of the current status of PX-478 in cancer treatment, with a focus on its application in treating pancreatic ductal adenocarcinoma (PDAC), lung cancer, breast cancer, glioma, and other kinds of cancer. This article discusses the mechanisms of action, pharmacokinetics, and pharmacodynamics of PX-478, as well as the findings of preclinical and clinical studies conducted to date. The evidence suggests that PX-478 has promising potential as a therapeutic agent for various cancer types. However, further research is needed to fully comprehend the compound's potential benefits and limitations and its optimal clinical application.

Keywords:

HIF-1α, PX-478, cancer therapy, combination treatment.

Zhang,L. (2023). HIF-1α inhibitor PX-478 for cancer therapy and other fields. Theoretical and Natural Science,21,258-263.
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References

[1]. “World Health Organization., “Cancer,” World Health Organization, 3 February 2022, <https://www.who.int/news-room/fact-sheets/detail/cancer> (20 May 2023).

[2]. Zhao, T., Ren, H., Jia, L., Chen, J., Xin, W., et al., “Inhibition of HIF-1 alpha by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma,” Oncotarget 6(4), 2250–2262 (2015).

[3]. Muz, B., de la Puente, P., Azab, F. and Azab, A. K., “The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy,” Hypoxia (Auckl) 3, 83–92 (2015).

[4]. Lee, K. and Kim, H. M., “A novel approach to cancer therapy using PX-478 as a HIF-1α inhibitor,” Arch. Pharm. Res. 34(10), 1583–1585 (2011).

[5]. Luo, F., Lu, F.-T., Cao, J.-X., Ma, W.-J., Xia, Z.-F., et al, “HIF-1 alpha inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer,” Cancer Lett. 531, 39–56 (2022).

[6]. Zhu, Y., Zang, Y., Zhao, F., Li, Z., Zhang, J., et al., “Inhibition of HIF-1α by PX-478 suppresses tumor growth of esophageal squamous cell cancer in vitro and in vivo,” Am J Cancer Res 7(5), 1198–1212 (2017).

[7]. Jacoby, J. J., Erez, B., Korshunova, M. V., Williams, R. R., Furutani, K., et al, “Treatment with HIF-1 alpha Antagonist PX-478 Inhibits Progression and Spread of Orthotopic Human Small Cell Lung Cancer and Lung Adenocarcinoma in Mice,” J. Thorac. Oncol. 5(7), 940–949 (2010).

[8]. Schwartz, D. L., Powis, G., Thitai-Kumar, A., He, Y., Bankson, J., et al., “The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects,” Molecular cancer therapeutics 8(4), 947–958 (2009).

[9]. Palayoor, S. T., Mitchell, J. B., Cerna, D., DeGraff, W., John-Aryankalayil, M., et al., “PX-478, an inhibitor of hypoxia-inducible factor-1α, enhances radiosensitivity of prostate carcinoma cells,” International Journal of Cancer 123(10), 2430–2437 (2008).

[10]. Schwartz, D. L., Bankson, J. A., Lemos, R., Jr., Lai, S. Y., Thittai, A. K., et al., “Radiosensitization and Stromal Imaging Response Correlates for the HIF-1 Inhibitor PX-478 Given with or without Chemotherapy in Pancreatic Cancer,” Molecular Cancer Therapeutics 9(7), 2057–2067 (2010).

[11]. Lang, M., Wang, X., Wang, H., Dong, J., Lan, C., et al., “Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma,” Cancer Letters 378(2), 87–96 (2016).

[12]. Parczyk, J., Ruhnau, J., Pelz, C., Schilling, M., Wu, H., et al., “Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines,” BMC Cancer 21(1), 481 (2021).

[13]. Li, H., Sun, X., Li, J., Liu, W., Pan, G., et al., “Hypoxia induces docetaxel resistance in triple-negative breast cancer via the HIF-1α/miR-494/Survivin signaling pathway,” Neoplasia 32, 100821 (2022).

[14]. Goodla, L. and Xue, X., “The Role of Inflammatory Mediators in Colorectal Cancer Hepatic Metastasis,” Cells 11(15), 2313 (2022).

[15]. Sun, S., Guo, C., Gao, T., Ma, D., Su, X., et al., “Hypoxia Enhances Glioma Resistance to Sulfasalazine-Induced Ferroptosis by Upregulating SLC7A11 via PI3K/AKT/HIF-1 alpha Axis,” Oxidative Med. Cell. Longev. 2022, 7862430 (2022).

[16]. Ryu, J.-S., Sim, S. H., Park, I. H., Lee, E. G., Lee, E. S., et al., “Integrative In Vivo Drug Testing Using Gene Expression Signature and Patient-Derived Xenografts from Treatment-Refractory HER2 Positive and Triple-Negative Subtypes of Breast Cancer,” Cancers 11(4), 574 (2019).

[17]. Sun, K., Halberg, N., Khan, M., Magalang, U. J. and Scherer, P. E., “Selective Inhibition of Hypoxia-Inducible Factor 1α Ameliorates Adipose Tissue Dysfunction,” Molecular and Cellular Biology 33(5), 904–917 (2013).

[18]. Villa-Roel, N., Ryu, K., Gu, L., Fernandez Esmerats, J., Kang, D.-W., et al, “Hypoxia inducible factor 1α inhibitor PX-478 reduces atherosclerosis in mice,” Atherosclerosis 344, 20–30 (2022).

[19]. Ilegems, E., Bryzgalova, G., Correia, J., Yesildag, B., Berra, E., Ruas, et al, “HIF-1α inhibitor PX-478 preserves pancreatic β cell function in diabetes,” Science Translational Medicine (2022).


Cite this article

Zhang,L. (2023). HIF-1α inhibitor PX-478 for cancer therapy and other fields. Theoretical and Natural Science,21,258-263.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

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About volume

Volume title: Proceedings of the 3rd International Conference on Biological Engineering and Medical Science

ISBN:978-1-83558-215-2(Print) / 978-1-83558-216-9(Online)
Editor:Alan Wang
Conference website: https://www.icbiomed.org/
Conference date: 2 September 2023
Series: Theoretical and Natural Science
Volume number: Vol.21
ISSN:2753-8818(Print) / 2753-8826(Online)

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References

[1]. “World Health Organization., “Cancer,” World Health Organization, 3 February 2022, <https://www.who.int/news-room/fact-sheets/detail/cancer> (20 May 2023).

[2]. Zhao, T., Ren, H., Jia, L., Chen, J., Xin, W., et al., “Inhibition of HIF-1 alpha by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma,” Oncotarget 6(4), 2250–2262 (2015).

[3]. Muz, B., de la Puente, P., Azab, F. and Azab, A. K., “The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy,” Hypoxia (Auckl) 3, 83–92 (2015).

[4]. Lee, K. and Kim, H. M., “A novel approach to cancer therapy using PX-478 as a HIF-1α inhibitor,” Arch. Pharm. Res. 34(10), 1583–1585 (2011).

[5]. Luo, F., Lu, F.-T., Cao, J.-X., Ma, W.-J., Xia, Z.-F., et al, “HIF-1 alpha inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer,” Cancer Lett. 531, 39–56 (2022).

[6]. Zhu, Y., Zang, Y., Zhao, F., Li, Z., Zhang, J., et al., “Inhibition of HIF-1α by PX-478 suppresses tumor growth of esophageal squamous cell cancer in vitro and in vivo,” Am J Cancer Res 7(5), 1198–1212 (2017).

[7]. Jacoby, J. J., Erez, B., Korshunova, M. V., Williams, R. R., Furutani, K., et al, “Treatment with HIF-1 alpha Antagonist PX-478 Inhibits Progression and Spread of Orthotopic Human Small Cell Lung Cancer and Lung Adenocarcinoma in Mice,” J. Thorac. Oncol. 5(7), 940–949 (2010).

[8]. Schwartz, D. L., Powis, G., Thitai-Kumar, A., He, Y., Bankson, J., et al., “The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects,” Molecular cancer therapeutics 8(4), 947–958 (2009).

[9]. Palayoor, S. T., Mitchell, J. B., Cerna, D., DeGraff, W., John-Aryankalayil, M., et al., “PX-478, an inhibitor of hypoxia-inducible factor-1α, enhances radiosensitivity of prostate carcinoma cells,” International Journal of Cancer 123(10), 2430–2437 (2008).

[10]. Schwartz, D. L., Bankson, J. A., Lemos, R., Jr., Lai, S. Y., Thittai, A. K., et al., “Radiosensitization and Stromal Imaging Response Correlates for the HIF-1 Inhibitor PX-478 Given with or without Chemotherapy in Pancreatic Cancer,” Molecular Cancer Therapeutics 9(7), 2057–2067 (2010).

[11]. Lang, M., Wang, X., Wang, H., Dong, J., Lan, C., et al., “Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma,” Cancer Letters 378(2), 87–96 (2016).

[12]. Parczyk, J., Ruhnau, J., Pelz, C., Schilling, M., Wu, H., et al., “Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines,” BMC Cancer 21(1), 481 (2021).

[13]. Li, H., Sun, X., Li, J., Liu, W., Pan, G., et al., “Hypoxia induces docetaxel resistance in triple-negative breast cancer via the HIF-1α/miR-494/Survivin signaling pathway,” Neoplasia 32, 100821 (2022).

[14]. Goodla, L. and Xue, X., “The Role of Inflammatory Mediators in Colorectal Cancer Hepatic Metastasis,” Cells 11(15), 2313 (2022).

[15]. Sun, S., Guo, C., Gao, T., Ma, D., Su, X., et al., “Hypoxia Enhances Glioma Resistance to Sulfasalazine-Induced Ferroptosis by Upregulating SLC7A11 via PI3K/AKT/HIF-1 alpha Axis,” Oxidative Med. Cell. Longev. 2022, 7862430 (2022).

[16]. Ryu, J.-S., Sim, S. H., Park, I. H., Lee, E. G., Lee, E. S., et al., “Integrative In Vivo Drug Testing Using Gene Expression Signature and Patient-Derived Xenografts from Treatment-Refractory HER2 Positive and Triple-Negative Subtypes of Breast Cancer,” Cancers 11(4), 574 (2019).

[17]. Sun, K., Halberg, N., Khan, M., Magalang, U. J. and Scherer, P. E., “Selective Inhibition of Hypoxia-Inducible Factor 1α Ameliorates Adipose Tissue Dysfunction,” Molecular and Cellular Biology 33(5), 904–917 (2013).

[18]. Villa-Roel, N., Ryu, K., Gu, L., Fernandez Esmerats, J., Kang, D.-W., et al, “Hypoxia inducible factor 1α inhibitor PX-478 reduces atherosclerosis in mice,” Atherosclerosis 344, 20–30 (2022).

[19]. Ilegems, E., Bryzgalova, G., Correia, J., Yesildag, B., Berra, E., Ruas, et al, “HIF-1α inhibitor PX-478 preserves pancreatic β cell function in diabetes,” Science Translational Medicine (2022).