Correction: Activity of the Heat Shock Protein 90 Inhibitor Ganetespib in Melanoma.
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ABSTRACT:
SUBMITTER: Wu X
PROVIDER: S-EPMC11361599 | biostudies-literature | 2024
REPOSITORIES: biostudies-literature
Publications
Correction: Activity of the Heat Shock Protein 90 Inhibitor Ganetespib in Melanoma.
Wu Xinqi X Marmarelis Melina E ME Stephen Hodi F F
PloS one 20240829 8
[This corrects the article DOI: 10.1371/journal.pone.0056134.]. ...[more]
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Project description:Hyperthermia is being used as a radio- and chemotherapy sensitizer for a growing range of tumor subtypes in the clinic. Its potential is limited, however, by the ability of cancer cells to activate a protective mechanism known as the heat stress response (HSR). The HSR is marked by the rapid overexpression of molecular chaperones, and recent advances in drug development make their inhibition an attractive option to improve the efficacy of hyperthermia-based therapies. Our previous in vitro work showed that a single, short co-treatment with a HSR (HSP90) inhibitor ganetespib prolongs and potentiates the effects of hyperthermia on DNA repair, enhances hyperthermic sensitization to radio- and chemotherapeutic agents, and reduces thermotolerance. In the current study, we first validated these results using an extended panel of cell lines and more robust methodology. Next, we examined the effects of hyperthermia and ganetespib on global proteome changes. Finally, we evaluated the potential of ganetespib to boost the efficacy of thermo-chemotherapy and thermo-radiotherapy in a xenograft murine model of cervix cancer. Our results revealed new insights into the effects of HSR inhibition on cellular responses to heat and show that ganetespib could be employed to increase the efficacy of hyperthermia when combined with radiation.
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Project description:HSP90 inhibition represents a promising route to cancer therapy, taking advantage of cancer cell-inherent proteotoxic stress. The HSP90-inhibitor ganetespib showed benefit in advanced clinical trials. This raises the need to identify the molecular determinants of treatment response. We tested the efficacy of ganetespib on a series of colorectal cancer (CRC)-derived cell lines and correlated their sensitivities with comprehensive gene expression analysis. Notably, the drug concentration required for 50% growth inhibition (IC50) varied up to 70-fold (from 36 to 2500 nM) between different cell lines. Correlating cell line-specific IC50s with the corresponding gene expression patterns revealed a strong association between ganetespib resistance (IC50>500 nM) and high expression of the UDP glucuronosyltransferase 1A (UGT1A) gene cluster. Moreover, CRC tumor samples showed a comparable distribution of UGT1A expression levels. The members of the UGT1A gene family are known as drug-conjugating liver enzymes involved in drug excretion, but their function in tumor cells is hardly understood. Chemically unrelated HSP90 inhibitors, for example, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), did not show correlation of drug sensitivities with UGT1A levels, whereas the ganetespib-related compound NVP-AUY922 did. When the most ganetespib-resistant cell line, HT29, was treated with ganetespib, the levels of HSP90 clients were unaffected. However, HT29 cells became sensitized to the drug, and HSP90 client proteins were destabilized by ganetespib upon siRNA-mediated UGT1A knockdown. Conversely, the most ganetespib-sensitive cell lines HCT116 and SW480 became more tolerant toward ganetespib upon UGT1A overexpression. Mechanistically, ganetespib was rapidly glucuronidated and excreted in resistant but not in sensitive CRC lines. We conclude that CRC cell-expressed UGT1A inactivates ganetespib and other resorcinolic Hsp90 inhibitors by glucuronidation, which renders the drugs unable to inhibit Hsp90 and thereby abrogates their biological activity. UGT1A levels in tumor tissues may be a suitable predictive biomarker to stratify CRC patients for ganetespib treatment.
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Project description:Drugs targeting heat shock protein 90 (Hsp90) have been extensively explored for their anticancer potential in advanced clinical trials. Nanoformulations have been an important drug delivery platform for the anticancer molecules like Hsp90 inhibitors. It has been reported that bovine serum albumin (BSA) nanoparticles (NPs) serve as carriers for anticancer drugs, which have been extensively explored for their therapeutic efficacy against cancers. Luminespib (also known as NVP-AUY922) is a new generation Hsp90 inhibitor that was introduced recently. It is one of the most studied Hsp90 inhibitors for a variety of cancers in Phase I and II clinical trials and is similar to its predecessors such as the ansamycin class of molecules. To our knowledge, nanoformulations for luminespib remain unexplored for their anticancer potential. In the present study, we developed aqueous dispensable BSA NPs for controlled delivery of luminespib. The luminespib-loaded BSA NPs were characterized by SEM, TEM, FTIR, XPS, UV-visible spectroscopy and fluorescence spectroscopy. The results suggest that luminespib interacts by non-covalent reversible interactions with BSA to form drug-loaded BSA NPs (DNPs). Our in vitro evaluations suggest that DNP-based aqueous nanoformulations can be used in both pancreatic (MIA PaCa-2) and breast (MCF-7) cancer therapy.
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Project description:Heat shock protein 90 (HSP90) is essential for cancer cells to assist the function of various oncoproteins, and it has been recognized as a promising target in cancer therapy. Although the HSP90 inhibitors in clinical trials have shown encouraging clinical efficacy, these agents induce heat shock response (HSR), which undermines their therapeutic effects. In this report, we detailed the pharmacologic properties of 4-(2-((1H-indol-3-yl)methylene)hydrazinyl)-N-(4-bromophenyl)-6-(3,5- dimethyl-1H -pyrazol-1-yl)-1,3,5-triazin-2-amine (X66), a novel and potent HSP90 inhibitor. X66 binds to the N-terminal domain in a different manner from the classic HSP90 inhibitors. Cellular study showed that X66 depleted HSP90 client proteins, resulted in cell cycle arrest and apoptosis, and inhibition of proliferation in cancer cell lines. X66 did not activate heat shock factor-1 (HSF-1) or stimulate transcription of HSPs. Moreover, the combination of X66 with HSP90 and proteasome inhibitors yielded synergistic cytotoxicity which was involved in X66-mediated abrogation of HSR through inhibition of HSF-1 activity. The intraperitoneal administration of X66 alone depleted client protein and inhibited tumor growth, and led to enhanced activity when combined with celastrol as compared to either agent alone in BT-474 xenograft model. Collectively, the HSP90 inhibitory action and the potent antitumor activity, with the anti-HSR action, promise X66 a novel HSP90-targeted agent, which merits further research and development.
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