Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor

Journal Article · Fri Sep 01 04:00:00 EDT 2017 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2017.07.006· OSTI ID:22722913

Li, Ting; Chen, Xin ^[1]; Dai, Xiao-Yang ^[2]; Wei, Bin ^[1]; Weng, Qin-Jie ^[2]; Chen, Xiuping; Ouyang, De-Fang; Yan, Ru ^[1]; Huang, Zhang-Jian; Jiang, Hu-Lin ^[3]; Zhu, Hong ^[2]; Lu, Jin-Jian ^[1]

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1. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao (China)
2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou (China)
3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing (China)

Heat shock protein 90 (Hsp90) is a critically conserved molecular chaperone protein and promising therapeutic target for cancer treatment. In this study, platycodin D (PD), a saponin isolated from traditional Chinese herb Platycodonis Radix, was identified as a novel Hsp90 inhibitor. We verified that PD did not affect the ATPase activity of Hsp90. However, PD disrupted the co-chaperone interaction of Hsp90/cell division cycle protein 37 (Cdc37) and subsequently degraded multiple Hsp90 client proteins without the feedback increase of Hsp70. In different genotypes of non-small cell lung cancer cells, co-treatment with the mTOR inhibitor Everolimus and PD enhanced antiproliferation activity and apoptotic effect. The feedback survival signal upon mTOR inhibition was fully terminated by the co-administration with PD through reduced epidermal growth factor receptor (EGFR) and insulin growth factor 1 receptor (IGF1R) expression, suppressed AKT activity, and reinforced 4E-BP1 inhibition. Our results not only identified PD as a novel Hsp90 inhibitor by disrupting the protein–protein interaction of Hsp90/Cdc37 complex, but also provided mechanistic insights into the ineffectiveness of mTOR inhibitors and identified therapeutic strategy for cancer treatment. - Highlights: • Platycodin D (PD) is a novel Hsp90 inhibitor by disrupting Hsp90/Cdc37 complex. • PD terminated the survival signal induced by mTOR inhibition via feedback blockade. • Combining mTOR inhibitor and PD together exhibited amplified anti-NSCLC effect.

• OSTI ID: 22722913
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Vol. 330; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CELL DIVISION
COMPLEXES
FEEDBACK
GROWTH FACTORS
HEAT-SHOCK PROTEINS
INHIBITION
NEOPLASMS
PLANT GROWTH