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.

Evaluation of the Heat Shock Protein 90 Inhibitor Ganetespib as a Sensitizer to Hyperthermia-Based Cancer Treatments

“…We also applied clonogenic survival assays to confirm that treatment is effective in a panel of 10 different cancer cell lines ( Figure 2 D), and that ganetespib can reduce the thermal dose and temperature required for sensitization ( Figure 3 C,D). These results are in line with multiple earlier studies relying on various inhibitors, treatment schedules and experimental models [ 44 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ]. It is thus clear that, at least in vitro, HSR disruption is an effective sensitization strategy.…”

Characteristics of the cancer stem cell niche and therapeutic strategies

“…Acriflavine, a potent inhibitor of HIF-1α dimerization, could disturb glucose metabolism in melanoma regardless of the hypoxic condition [ 136 ]. Chetomin, another inhibitor of HIF-1α, could suppress the transcriptional activity via targeting p300 recruitment [ 137 ]. Furthermore, other agents, such as wortmannin, temsirolimus and camptothecin, have been proved to inhibit HIF-1α protein translation by targeting corresponding genes [ 138 ].…”

Hnrnpk maintains chondrocytes survival and function during growth plate development via regulating Hif1α-glycolysis axis

“…4J ). Then, the Hnrnpk fl/fl chondrocytes were treated with Chetomin [ 35 ], Hif1α inhibitor, after being infected with Ad-GFP or Ad-Cre under hypoxic condition, and the decrease of Sox9 and increase of Mmp13 were significantly reversed in the Hnrnpk ablation chondrocytes (Fig. 4K ).…”