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

Saber, Sameh; Hasan, Alexandru Madalin; Mohammed, Osama A.; Saleh, Lobna A.; Hashish, Abdullah A.; Alamri, Mohannad Mohammad S.; Al-Ameer, Ahmed Y.; Alfaifi, Jaber; Senbel, Ahmed; Aboregela, Adel Mohamed; Khalid, Tarig Babikir Algak; Abdel-Reheim, Mustafa Ahmed; Cavalu, Simona

doi:10.1016/j.biopha.2023.114918

Cited by 11 publications

(5 citation statements)

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“…This observation could explain the efficacy of combination treatment observed in the XTT assay for BHT-101 cells. These results are also in line with a recent publication where the HSP90 inhibitor Ganetespib augments sorafenib efficacy via necroptosis induction in hepatocellular carcinoma 30 .…”

Section: Discussionsupporting

confidence: 91%

Combination therapy of tyrosine kinase inhibitor sorafenib with the HSP90 inhibitor onalespib as a novel treatment regimen for thyroid cancer

Mortensen,

Berglund,

Hariri

et al. 2023

Sci Rep

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Thyroid cancer is the most common endocrine malignancy, affecting nearly 600,000 new patients worldwide. Treatment with the BRAF inhibitor sorafenib partially prolongs progression-free survival in thyroid cancer patients, but fails to improve overall survival. This study examines enhancing sorafenib efficacy by combination therapy with the novel HSP90 inhibitor onalespib. In vitro efficacy of sorafenib and onalespib monotherapy as well as in combination was assessed in papillary (PTC) and anaplastic (ATC) thyroid cancer cells using cell viability and colony formation assays. Migration potential was studied in wound healing assays. The in vivo efficacy of sorafenib and onalespib therapy was evaluated in mice bearing BHT-101 xenografts. Sorafenib in combination with onalespib significantly inhibited PTC and ATC cell proliferation, decreased metabolic activity and cancer cell migration. In addition, the drug combination approach significantly inhibited tumor growth in the xenograft model and prolonged the median survival. Our results suggest that combination therapy with sorafenib and onalespib could be used as a new therapeutic approach in the treatment of thyroid cancer, significantly improving the results obtained with sorafenib as monotherapy. This approach has the potential to reduce treatment adaptation while at the same time providing therapeutic anti-cancer benefits such as reducing tumor growth and metastatic potential.

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Section: Discussionsupporting

confidence: 91%

Combination therapy of tyrosine kinase inhibitor sorafenib with the HSP90 inhibitor onalespib as a novel treatment regimen for thyroid cancer

Mortensen,

Berglund,

Hariri

et al. 2023

Sci Rep

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“…The experimentally determined CTC 50 value for the combination of both drugs was also plotted. Furthermore, the combination index was confirmed using the formula described by Saber, et al [ 60 ].…”

Section: Methodsmentioning

confidence: 99%

Alvespimycin Exhibits Potential Anti-TGF-β Signaling in the Setting of a Proteasome Activator in Rats with Bleomycin-Induced Pulmonary Fibrosis: A Promising Novel Approach

Mohammed,

Abdel-Reheim,

Saleh

et al. 2023

Pharmaceuticals

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Idiopathic pulmonary fibrosis (IPF) is an irreversible and life-threatening lung disease of unknown etiology presenting only a few treatment options. TGF-β signaling orchestrates a cascade of events driving pulmonary fibrosis (PF). Notably, recent research has affirmed the augmentation of TGF-β receptor (TβR) signaling via HSP90 activation. HSP90, a molecular chaperone, adeptly stabilizes and folds TβRs, thus intricately regulating TGF-β1 signaling. Our investigation illuminated the impact of alvespimycin, an HSP90 inhibitor, on TGF-β-mediated transcriptional responses by inducing destabilization of TβRs. This outcome stems from the explicit interaction of TβR subtypes I and II with HSP90, where they are clients of this cellular chaperone. It is worth noting that regulation of proteasome-dependent degradation of TβRs is a critical standpoint in the termination of TGF-β signal transduction. Oleuropein, the principal bioactive compound found in Olea europaea, is acknowledged for its role as a proteasome activator. In this study, our aim was to explore the efficacy of a combined therapy involving oleuropein and alvespimycin for the treatment of PF. We employed a PF rat model that was induced by intratracheal bleomycin infusion. The application of this dual therapy yielded a noteworthy impediment to the undesired activation of TGF-β/mothers against decapentaplegic homologs 2 and 3 (SMAD2/3) signaling. Consequently, this novel combination showcased improvements in both lung tissue structure and function while also effectively restraining key fibrosis markers such as PDGF-BB, TIMP-1, ACTA2, col1a1, and hydroxyproline. On a mechanistic level, our findings unveiled that the antifibrotic impact of this combination therapy likely stemmed from the enhanced degradation of both TβRI and TβRII. In conclusion, the utilization of proteasomal activators in conjunction with HSP90 inhibitors ushers in a promising frontier for the management of PF.

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“…Interestingly, the effect of digoxin as an HIF-1 inhibito in human breast cancer tissues is under investigation through phase II clinical trials [86] Moreover, Ganetespib, a novel and potent inhibitor of heat shock protein 90 (HSP90), ha shown efficacy in suppressing HIF-1 as well [87]. This medicine has demonstrated prom ising efficacy in the treatment of various types of malignancies, including non-small cel lung cancer, breast cancer, and melanoma [88]. The ability of this medication to affec many pathways that are often altered in cancer makes it an intriguing candidate for over coming resistance to other therapeutic methods [89].…”

Section: Inhibitors Of Hifα Protein Synthesismentioning

confidence: 99%

Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation

Qannita,

Alalami,

Harb

et al. 2024

Pharmaceuticals

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Hypoxia-inducible factor-1 (HIF-1) is a key regulator for balancing oxygen in the cells. It is a transcription factor that regulates the expression of target genes involved in oxygen homeostasis in response to hypoxia. Recently, research has demonstrated the multiple roles of HIF-1 in the pathophysiology of various diseases, including cancer. It is a crucial mediator of the hypoxic response and regulator of oxygen metabolism, thus contributing to tumor development and progression. Studies showed that the expression of the HIF-1α subunit is significantly upregulated in cancer cells and promotes tumor survival by multiple mechanisms. In addition, HIF-1 has potential contributing roles in cancer progression, including cell division, survival, proliferation, angiogenesis, and metastasis. Moreover, HIF-1 has a role in regulating cellular metabolic pathways, particularly the anaerobic metabolism of glucose. Given its significant and potential roles in cancer development and progression, it has been an intriguing therapeutic target for cancer research. Several compounds targeting HIF-1-associated processes are now being used to treat different types of cancer. This review outlines emerging therapeutic strategies that target HIF-1 as well as the relevance and regulation of the HIF-1 pathways in cancer. Moreover, it addresses the employment of nanotechnology in developing these promising strategies.

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

Cited by 11 publications

References 50 publications

Combination therapy of tyrosine kinase inhibitor sorafenib with the HSP90 inhibitor onalespib as a novel treatment regimen for thyroid cancer

Combination therapy of tyrosine kinase inhibitor sorafenib with the HSP90 inhibitor onalespib as a novel treatment regimen for thyroid cancer

Alvespimycin Exhibits Potential Anti-TGF-β Signaling in the Setting of a Proteasome Activator in Rats with Bleomycin-Induced Pulmonary Fibrosis: A Promising Novel Approach

Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation

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