Chetomin, a Hsp90/HIF1α pathway inhibitor, effectively targets lung cancer stem cells and non-stem cells

ABSTRACT

Non-small cell lung cancer (NSCLC) remains recalcitrant to effective treatment due to tumor relapse and acquired resistance. Cancer stem cells (CSCs) are believed to be one mechanism for relapse and resistance and are consequently considered promising drug targets. We report that chetomin, an active component of Chaetomium globosum, blocks heat shock protein 90/hypoxia-inducible factor 1 alpha (Hsp90/HIF1α) pathway activity. Chetomin also attenuated sphere-forming, a stem cell-like characteristic, of NSCLC CSCs (at ~ nM range) and the proliferation of non-CSCs NSCLC cultures and chemoresistant sublines (at ~ μM range). At these concentrations, chetomin exerted a marginal influence on noncancerous cells originating from several organs. Chetomin markedly decreased in vivo tumor formation in a spontaneous Kras^LA1 lung cancer model, flank xenograft models, and a tumor propagation flank implanted model at doses that did not produce an observable toxicity to the animals. Chetomin blocked Hsp90/HIF1α pathway activity via inhibiting the Hsp90-HIF1α binding interaction without affecting Hsp90 or Hsp70 protein levels. This study advocates chetomin as a Hsp90/HIF1α pathway inhibitor and a potent, nontoxic NSCLC CSC-targeting molecule.

KEYWORDS:

• Chetomin
• lung cancer
• cancer stem cells
• heat shock protein

Author Contributions

Conceived and designed the study: TW, NW, and XJW.

Performed the experimental procedures: SPM, QYD, HYG, XCL, YBS, YY, WL, YC, and CLZ.

Analyzed the data: TW, NW, YBS, and XXW.

Drafted the manuscript: XJW and YQC.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [81772493]; Science and Technology Program of Anhui Province [2017070503B037, YDZX20183400002554].