Pharmacological Regulation Possibilities of HIF for Its’ Mediated Pathologies in Clinical Practice
- Authors: Novikov V.E.1, Levchenkova O.S.1
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Affiliations:
- Smolensk State Medical University
- Issue: Vol 79, No 3 (2024)
- Pages: 261-270
- Section: PHARMACOLOGY: CURRENT ISSUES
- Published: 15.08.2024
- URL: https://vestnikramn.spr-journal.ru/jour/article/view/17946
- DOI: https://doi.org/10.15690/vramn17946
- ID: 17946
Cite item
Abstract
The review is devoted to the experimental and clinical data analysis about the effectiveness and safety of drugs whose main target is the hypoxia-inducible factor HIF. The use of HIF inhibitors continues to be widely researched and is trying to enter practice in the treatment of cancers, such as the HIF-2α inhibitor belzutifan, which is approved for treatment of cancers associated with von Hippel–Lindau disease (VHL). HIF stabilizers can initiate preconditioning and be used in acute predictable myocardial or cerebral ischemia (during cardiac or vascular surgery). Long-term administration of some of them, in particular prolyl hydroxylase inhibitors, in the treatment of renal anemia cannot exclude the activation of neoangiogenesis, which is associated with the risk of pro-oncogenic effect as well as an increased risk of thrombosis and cardiovascular events.
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About the authors
Vasiliy E. Novikov
Smolensk State Medical University
Author for correspondence.
Email: novikov.farm@yandex.ru
ORCID iD: 0000-0002-0953-7993
MD, PhD, Professor
Russian Federation, SmolenskOlga S. Levchenkova
Smolensk State Medical University
Email: levchenkova-o@yandex.ru
ORCID iD: 0000-0002-9595-6982
SPIN-code: 2888-6150
MD, PhD, Associate Professor
Russian Federation, SmolenskReferences
- Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–732. doi: https://doi.org/10.1038/nrc1187
- Semenza GL. Pharmacologic targeting of Hypoxia-inducible factors. Ann Rev Pharmacol Toxicol. 2019;59(1):379–403. doi: https://doi.org/10.1146/annurev-pharmtox-010818-021637
- Fandrey J, Schödel J, Eckardt K, et al. Now a Nobel gas: oxygen. Pflügers Arch. 2019;471(11–12):1343–1358. doi: https://doi.org/10.1007/s00424-019-02334-8
- Лукьянова Л.Д. Сигнальные механизмы гипоксии. — М.: РАН, 2019. [Luk’janova L.D. Signal’nye mehanizmy gipoksii. Moscow: RAN; 2019. (In Russ.)]
- Albadari N, Deng S, Li W. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opin Drug Discov. 2019;14(7):667–682. doi: https://doi.org/10.1080/17460441.2019.1613370
- Левченкова О.С., Новиков В.Е. Возможности фармакологического прекондиционирования // Вестник РАМН. — 2016. — Т. 71. — № 1. — С. 16–24. [Levchenkova OS, Novikov VE. Possibilities of pharmacological preconditioning. Annals of the Russian Academy of Medical Sciences. 2016;71(1):16–24. (In Russ.)] doi: https://doi.org/10.15690/vramn626
- Хушпульян Д.М., Никулин С.В., Чубарь Т.А., и др. Гены «быстрого» отклика при действии ингибиторов HIF пролилгидроксилазы // Вестник Московского университета. Серия 2. Химия. — 2021. — Т. 62. — № 3. — С. 213–222. [Hushpulian DM, Nikulin SV, Chubar TA, et al. Fast responding genes to HIF prolyl hydroxylase inhibitors. Moscow University Chemistry Bulletin. 2021;62(3):213–222. (In Russ.)]
- Semenza GL. Breakthrough science: hypoxia-inducible factors, oxygen sensing, and disorders of hematopoiesis. Blood. 2022;139(16):2441–2449. doi: https://doi.org/10.1182/blood.2021011043
- Новиков В.Е., Левченкова О.С. Перспективы применения ингибиторов фактора адаптации к гипоксии в онкологии // Вестник Смоленской государственной медицинской академии. — 2015. — Т. 14. — № 3. — С. 21–26. [Novikov VE, Levchenkova OS. Prospects of inhibitors of adaptation to hypoxia in cancer medicine. Vestnik of the Smolensk State Medical Academy. 2015;3(14):21–26. (In Russ.)]
- Semenza GL. Mechanisms of Breast Cancer Stem Cell Specification and Self-Renewal Mediated by Hypoxia-Inducible Factor 1. Stem Cells Transl Med. 2023;12(12):783–790. doi: https://doi.org/10.1093/stcltm/szad061
- Infantino V, Santarsiero A, Convertini P, et al. Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target. Int J Mol Sci. 2021;22(11):5703. doi: https://doi.org/10.3390/ijms22115703
- Kao TW, Bai GH, Wang TL, et al. Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance. J Exp Clin Cancer Res. 2023;42(1):171. doi: https://doi.org/10.1186/s13046-023-02724-y
- Chen Y, Liu L, Xia L, et al. TRPM7 silencing modulates glucose metabolic reprogramming to inhibit the growth of ovarian cancer by enhancing AMPK activation to promote HIF-1α degradation. J Exp Clin Cancer Res. 2022;41(1):44. doi: https://doi.org/10.1186/s13046-022-02252-1
- Elzakra N, Kim Y. HIF-1α Metabolic Pathways in Human Cancer. Adv Exp Med Biol. 2021;1280:243–260. doi: https://doi.org/10.1007/978-3-030-51652-9_17
- Domènech M, Hernández A, Plaja A, et al. Hypoxia: The Cornerstone of Glioblastoma. Int J Mol Sci. 2021;22(22):12608. doi: https://doi.org/10.3390/ijms222212608
- Wicks EE, Semenza GL. Hypoxia-inducible factors: cancer progression and clinical translation. J Clin Invest. 2022;132(11):e159839. doi: https://doi.org/10.1172/JCI159839
- Rani S, Roy S, Singh M, Kaithwas G. Regulation of Transactivation at C-TAD Domain of HIF-1α by Factor-Inhibiting HIF-1α (FIH-1): A Potential Target for Therapeutic Intervention in Cancer. Oxid Med Cell Longev. 2022:2407223. doi: https://doi.org/10.1155/2022/2407223
- Abdelhaleem EF, Kassab AE, El-Nassan HB, et al. Design, synthesis, and biological evaluation of new celecoxib analogs as apoptosis inducers and cyclooxygenase-2 inhibitors. Arch Pharm (Weinheim). 2022;355(11):e2200190. doi: https://doi.org/10.1002/ardp.202200190
- Zhang M, Zhang Y, Ding Y, et al. Regulating the Expression of HIF-1α or lncRNA: Potential Directions for Cancer Therapy. Cells. 2022;11(18):2811. doi: https://doi.org/10.3390/cells11182811
- Zhang H, Wei S, Zhang Y, et al. Improving cellular uptake and bioavailability of periplocymarin-linoleic acid prodrug by combining PEGylated liposome. Drug Deliv. 2022;29(1):2491–2497. doi: https://doi.org/10.1080/10717544.2022.2104406
- Rahmanian-Devin P, Baradaran Rahimi V, Jaafari MR, et al. Noscapine, an Emerging Medication for Different Diseases: A Mechanistic Review. Evid Based Complement Alternat Med. 2021:8402517. doi: https://doi.org/10.1155/2021/8402517
- Pang Y, Yang C, Schovanek J, et al. Anthracyclines suppress pheochromocytoma cell characteristics, including metastasis, through inhibition of the hypoxia signaling pathway. Oncotarget. 2017;8(14):22313–22324. doi: https://doi.org/10.18632/oncotarget.16224
- Li Y, Luo J, Lin MT, et al. Co-Delivery of Metformin Enhances the Antimultidrug Resistant Tumor Effect of Doxorubicin by Improving Hypoxic Tumor Microenvironment. Mol Pharm. 2019;16(7):2966–2979. doi: https://doi.org/10.1021/acs.molpharmaceut.9b00199
- Giannopoulou AI, Kanakoglou DS, Piperi C. Transcription Factors with Targeting Potential in Gliomas. Int J Mol Sci. 2022;23(7):3720. doi: https://doi.org/10.3390/ijms23073720
- Toledo RA, Jimenez C, Armaiz-Pena G, et al. Hypoxia-Inducible Factor 2 Alpha (HIF2α) Inhibitors: Targeting Genetically Driven Tumor Hypoxia. Endocr Rev. 2023;44(2):312–322. doi: https://doi.org/10.1210/endrev/bnac025
- Sebestyén A, Kopper L, Dankó T, et al. Hypoxia Signaling in Cancer: From Basics to Clinical Practice. Pathol Oncol Res. 2021;27:1609802. doi: https://doi.org/10.3389/pore.2021.1609802
- Zhang Y, Nguyen CC, Zhang NT, et al. Neurological applications of belzutifan in von Hippel-Lindau disease. Neuro Oncol. 2023;25(5):827–838. doi: https://doi.org/10.1093/neuonc/noac234
- Choi WW, Boland JL, Kalola A, et al. Belzutifan (MK-6482): Biology and Clinical Development in Solid Tumors. Curr Oncol Rep. 2023; 25(2):123–129. doi: https://doi.org/10.1007/s11912-022-01354-5
- Rashid M, Zadeh LR, Baradaran B, et al. Up-down regulation of HIF-1α in cancer progression. Gene. 2021;798:145796. doi: https://doi.org/10.1016/j.gene.2021.145796
- Lee SH, Golinska M, Griffiths JR. HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells. Cells. 2021;10(9):2371. doi: https://doi.org/10.3390/cells10092371
- Nagle DG, Yu-Dong Z. Natural product-derived small molecule activators of Hypoxia-inducible factor-1 (HIF-1). Curr Pharm Des. 2006;12(21):2673–2688. doi: https://doi.org/10.2174/138161206777698783
- Sato T, Takeda N. The roles of HIF-1α signaling in cardiovascular diseases. J Cardiol. 2023;81(2):202–208. doi: https://doi.org/10.1016/j.jjcc.2022.09.002
- Davis CK, Jain SA, Bae O, et al. Hypoxia mimetic agents for ischemic stroke. Front Cell Dev Biol. 2019;6:175. doi: https://doi.org/10.3389/fcell.2018.00175
- Sergesketter AR, Cason RW, Ibrahim MM, et al. Perioperative treatment with a prolyl hydroxylase inhibitor reduces necrosis in a rat ischemic skin flap model. Plast Reconstr Surg. 2019;143(4):769e–779e. doi: https://doi.org/10.1097/PRS.0000000000005441
- Savyuk M, Krivonosov M, Mishchenko T, et al. Neuroprotective effect of HIF Prolyl Hydroxylase inhibition in an in vitro hypoxia model. Antioxidants (Basel). 2020;9(8):662. doi: https://doi.org/10.3390/antiox9080662
- Chen J, Lin X, Yao C, et al. Transplantation of Roxadustat-preconditioned bone marrow stromal cells improves neurological function recovery through enhancing grafted cell survival in ischemic stroke rats. CNS Neurosci Ther. 2022;28(10):1519–1531. doi: https://doi.org/10.1111/cns.13890
- Deguchi H, Ikeda M, Ide T, et al. Roxadustat Markedly Reduces Myocardial Ischemia Reperfusion Injury in Mice. Circ J. 2020;84(6):1028–1033. doi: https://doi.org/10.1253/circj.CJ-19-1039
- Верткин А.Л., Прохорович Е.А., Кнорринг Г.Ю. Хроническая болезнь почек: диагностика, ведение и терапия ассоциированной анемии // Терапия. — 2022. — Т. 8. — № 6. — С. 109–119. [Vertkin AL, Prokhorovich ЕА, Knorring GYu. Diagnosis, management of chronic kidney disease and therapy of anemia associated with CKD. Therapy. 2022;8(6):109–119. (In Russ.)] doi: https://doi.org/10.18565/therapy.2022.6.109-119
- Ogawa C, Tsuchiya K, Maeda K. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors and Iron Metabolism. Int J Mol Sci. 2023;24(3):3037. doi: https://doi.org/10.3390/ijms24033037
- Мельник А.А. Гипоксией индуцированный фактор для лечения анемии при хронической болезни почек // Почки. — 2018. — Т. 7. — № 4. — С. 311–321. [Melnyk AA. Hypoxia-induced factor for the treatment of anemia in chronic kidney disease. Kidneys. 2018;7(4):311–321. (In Russ.)] doi: https://doi.org/10.22141/2307-1257.7.4.2018.148522
- Mahajan R, Samanthula G, Srivastava S, Asthana A. A critical review of Roxadustat formulations, solid state studies, and analytical methodology. Heliyon. 2023;9(6):e16595. doi: https://doi.org/10.1016/j.heliyon.2023.e16595
- Dhillon S. Roxadustat: First Global Approval. Drugs. 2019;79(5):563–572. doi: https://doi.org/10.1007/s40265-019-01077-1
- Chen H, Cheng Q, Wang J, et al. Long-term efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta-analysis including 13,146 patients. J Clin Pharm Ther. 2021;46(4):999–1009. doi: https://doi.org/10.1111/jcpt.13385
- Hirota K. HIF-α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: A Comprehensive Review. Biomedicines. 2021;9(5):468. doi: https://doi.org/10.3390/biomedicines9050468
- Yang J, Xing J, Zhu X, et al. Effects of hypoxia-inducible factor-prolyl hydroxylase inhibitors vs. erythropoiesis-stimulating agents on iron metabolism in non-dialysis-dependent anemic patients with CKD: A network meta-analysis. Front Endocrinol (Lausanne). 2023;14:1131516. doi: https://doi.org/10.3389/fendo.2023.1131516
- Куркин Д.В., Бакулин Д.А., Абросимова Е.Е., и др. Фактор, индуцируемый гипоксией, и ингибиторы пролилгидроксилазы — новая фармакологическая мишень и класс лекарственных препаратов, стимулирующих эритропоэз и не только // Успехи физиологических наук. — 2022. — Т. 53. — № 3. — С. 15–44. [Kurkin DV, Bakulin DA, Abrosimova EE, et al. HIF and Prolyl Hydroxylase Inhibitors — a New Pharmacological Target and a Medicinal Drugs Class Stimulating Not Only Erythropoiesis, But More. Physics-Uspekhi. 2022;53(3):15–44. (In Russ.)] doi: https://doi.org/10.31857/S0301179822030067
- Negri AL. Role of prolyl hydroxylase/HIF-1 signaling in vascular calcification. Clin Kidney J. 2022;16(2):205–209. doi: https://doi.org/10.1093/ckj/sfac224
- Georgy M, Salhiyyah K, Yacoub MH, et al. Role of hypoxia inducible factor HIF-1α in heart valves. Glob Cardiol Sci Pract. 2023;2023(2):e202309. doi: https://doi.org/10.21542/gcsp.2023.9
- Chen J, Shou X, Xu Y, et al. A network meta-analysis of the efficacy of hypoxia-inducible factor prolyl-hydroxylase inhibitors in dialysis chronic kidney disease. Aging (Albany NY). 2023;15(6):2237–2274. doi: https://doi.org/10.18632/aging.204611
- Li QY, Xiong QW, Yao X, et al. Roxadustat: Do we know all the answers? Biomol Biomed. 2023;23(3):354–363. doi: https://doi.org/10.17305/bb.2022.8437
- Cheng S, Zhou T, Yu L, et al. Comparison between the influence of roxadustat and recombinant human erythropoietin treatment on blood pressure and cardio-cerebrovascular complications in patients undergoing peritoneal dialysis. Front Med (Lausanne). 2023;10:1166024. doi: https://doi.org/10.3389/fmed.2023.1166024
- Zhou Q, Mao M, Li J, et al. The efficacy and safety of roxadustat for anemia in patients with dialysis-dependent chronic kidney disease: a systematic review and meta-analysis. Ren Fail. 2023;45(1):2195011. doi: https://doi.org/10.1080/0886022X.2023.2195011
- Chen D, Niu Y, Liu F, et al. Safety of HIF prolyl hydroxylase inhibitors for anemia in dialysis patients: a systematic review and network meta-analysis. Front Pharmacol. 2023;14:1163908. doi: https://doi.org/10.3389/fphar.2023.1163908
- Семочкин С.В. Практические аспекты применения эритропоэзстимулирующих препаратов у пациентов онкогематологического профиля // Медицинский совет. — 2022. — Т. 16. — № 22. — С. 74–84. [Semochkin SV. Practical aspects of the use of erythropoiesis-stimulating agent in patients with hematological malignancy. Meditsinskiy sovet = Medical Council. 2022;16(22):74–84. (In Russ.)] doi: https://doi.org/10.21518/2079-701X-2022-16-22-1
- Gul K, Zaman N, Azam SS. Roxadustat and its failure: A comparative dynamic study. J Mol Graph Model. 2023;120:108422. doi: https://doi.org/10.1016/j.jmgm.2023.108422
- Besarab A, Chernyavskaya E, Motylev I, et al. Roxadustat (FG-4592): correction of anemia in incident dialysis patients. J Am Soc Nephrol. 2016;27(4):1225. doi: https://doi.org/10.1681/ASN.2015030241
- Barratt J, Dellanna F, Portoles J, et al. Safety of Roxadustat Versus Erythropoiesis-Stimulating Agents in Patients with Anemia of Non-dialysis-Dependent or Incident-to-Dialysis Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies. Adv Ther. 2023;40(4):1546–1559. doi: https://doi.org/10.1007/s12325-023-02433-0
- Semenza GL. Regulation of Erythropoiesis by the Hypoxia-Inducible Factor Pathway: Effects of Genetic and Pharmacological Perturbations. Annu Rev Med. 2023;74:307–319. doi: https://doi.org/10.1146/annurev-med-042921-102602
- Kouki Y, Okada N, Saga K, et al. Disproportionality Analysis on Hypothyroidism With Roxadustat Using the Japanese Adverse Drug Event Database. J Clin Pharmacol. 2023;63(10):1141–1146. doi: https://doi.org/10.1002/jcph.2300
- Fukui K, Shinozaki Y, Kobayashi H, et al. JTZ-951 (enarodustat), a hypoxia-inducibe factor prolyl hydroxylase inhibitor, stabilizes HIF-α protein and induces erythropoiesis without effects on the function of vascular endothelial growth factor. Eur J Pharmacol. 2019;859:172532. doi: https://doi.org/10.1016/j.ejphar.2019.172532
- Bailey CK, Caltabiano S, Cobitz AR, et al. A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis. BMC Nephrol. 2019;20(1):372. doi: https://doi.org/10.1186/s12882-019-1547-z
- Adams DF, Watkins MS, Durette L, et al. Carcinogenicity Assessment of Daprodustat (GSK1278863), a Hypoxia-Inducible Factor (HIF)-Prolyl Hydroxylase Inhibitor. Toxicol Pathol. 2020;48(2):362–378. doi: https://doi.org/10.1177/0192623319880445
- Kachamakova-Trojanowska N, Podkalicka P, Bogacz T, et al. HIF-1 stabilization exerts anticancer effects in breast cancer cells in vitro and in vivo. Biochem Pharmacol. 2020;175:113922. doi: https://doi.org/10.1016/j.bcp.2020.113922
- Waldum H. Dysfunction of von-Hippel Lindau factor causes reduced degradation of HIF leading to renal cancer. Hypoxia-inducible factor-prolyl hydroxylase enzyme inhibitors also lessen HIF destruction and could therefore increase renal cancer. Front Pharmacol. 2023;14:1170796. doi: https://doi.org/10.3389/fphar.2023.1170796
- Шутов Е.В., Горелова Е.Н., Сороколетов С.М. Ингибиторы пролилгидроксилазы индуцируемого гипоксией фактора в лечении анемии больных с хронической болезнью почек // Эффективная фармакотерапия. — 2022. — Т. 18. — № 3. — С. 22–28. [Shutov EV, Gorelova EN, Sorokoletov SM. Hypoxia-inducible factor prolyl hydroxylase inhibitors in the treatment of anemia in patients with chronic kidney disease. Effektivnaya farmakoterapiya. 2022;18(3):22–28. (In Russ.)]. doi: https://doi.org/10.33978/2307-3586-2022-18-3-22-28
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