Ganetespib (STA-9090) augments sorafenib efficacy via necroptosis induction in hepatocellular carcinoma: Implications from preclinical data for a novel therapeutic approach.

Autor: Saber S; Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt. Electronic address: sampharm81@gmail.com., Hasan AM; Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania. Electronic address: alexhasy@yahoo.com., Mohammed OA; Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt; Department of Clinical Pharmacology, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia. Electronic address: osamaabbass@med.asu.edu.eg., Saleh LA; Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt., Hashish AA; Basic Medical Sciences Department, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia; Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt., Alamri MMS; Department of Family Medicine, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia., Al-Ameer AY; Department of General Surgery, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia., Alfaifi J; Department of Child Health, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia., Senbel A; Department of General Surgery, College of medicine, University of Bisha, Bisha 61922, Saudi Arabia; Department of Surgical Oncology, Oncology Center, Faculty of Medicine, Mansoura University, Mansoura 35516 Egypt., Aboregela AM; Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Egypt., Khalid TBA; Basic Medical Sciences Department, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia., Abdel-Reheim MA; Department of Pharmaceutical sciences, College of Pharmacy, Shaqra University, Aldawadmi 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt. Electronic address: m.ahmed@su.edu.sa., Cavalu S; Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Aug; Vol. 164, pp. 114918. Date of Electronic Publication: 2023 May 20.
DOI: 10.1016/j.biopha.2023.114918
Abstrakt: Sorafenib, a multikinase inhibitor, is a first-line treatment for advanced hepatocellular carcinoma, but its long-term effectiveness is limited by the emergence of resistance mechanisms. One such mechanism is the reduction of microvessel density and intratumoral hypoxia caused by prolonged sorafenib treatment. Our research has demonstrated that HSP90 plays a critical role in conferring resistance to sorafenib in HepG2 cells under hypoxic conditions and N-Nitrosodiethylamine-exposed mice as well. This occurs through the inhibition of necroptosis on the one hand and the stabilization of HIF-1α on the other hand. To augment the effects of sorafenib, we investigated the use of ganetespib, an HSP90 inhibitor. We found that ganetespib activated necroptosis and destabilized HIF-1α under hypoxia, thus enhancing the effectiveness of sorafenib. Additionally, we discovered that LAMP2 aids in the degradation of MLKL, which is the mediator of necroptosis, through the chaperone-mediated autophagy pathway. Interestingly, we observed a significant negative correlation between LAMP2 and MLKL. These effects resulted in a reduction in the number of surface nodules and liver index, indicating a regression in tumor production rates in mice with HCC. Furthermore, AFP levels decreased. Combining ganetespib with sorafenib showed a synergistic cytotoxic effect and resulted in the accumulation of p62 and inhibition of macroautophagy. These findings suggest that the combined therapy of ganetespib and sorafenib may offer a promising approach for the treatment of hepatocellular carcinoma by activating necroptosis, inhibiting macroautophagy, and exhibiting a potential antiangiogenic effect. Overall, continued research is critical to establish the full therapeutic potential of this combination therapy.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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