Natura-alpha targets forkhead box M1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion

Yirong Li, Martin Ligr, James P. McCarron, Garrett Daniels, David Zhang, Xin Zhao, Fei Ye, Jinhua Wang, Xiaomei Liu, Iman Osman, Simon K. Mencher, Hebert Lepor, Long G. Wang, Peng Lee

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Purpose: The development of new effective therapeutic agents with minimal side effects for prostate cancer (PC) treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine - Qing Dai (Indigo naturalis), has been used to treat leukemia for decades. However, the anticancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in PC. Experimental Design: The growth kinetics and invasion ability of on human PC cell lines with or without Natura-alpha treatment were measured by cell proliferation and invasion assays. The antitumor effects of Natura-alpha were examined in nude mice tumor xenograft models, and in a patient with advanced hormone-refractory metastatic PC. Signal network proteins targeted by Natura-alpha were analyzed by using proteomic pathway array analysis (PPAA) on xenografts. Results: Natura-alpha inhibited the growth of both androgen-dependent (LNCaP) and androgen-independent (LNCaP-AI, PC-3, and DU145) PC cells with IC50 between 4 to 10 mmol/L, and also inhibited invasion of androgen-independent PC cells. Its antitumor effects were further evident in in vivo tumor reduction in androgen-dependent and androgen-independent nude mice tumor xenograft models and reduced tumor volume in the patient with hormone refractory metastatic PC. PPAA revealed that antiproliferative and antiinvasive activities of Natura-alpha on PC might primarily be through its downregulation of Forkhead box M1 (FOXM1) protein. Forced overexpression of FOXM1 largely reversed the inhibition of growth and invasion by Natura-alpha. Conclusion: Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone-sensitive and hormone-refractory PC with minimal side effects.

Original languageEnglish (US)
Pages (from-to)4414-4424
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number13
DOIs
StatePublished - Jul 1 2011
Externally publishedYes

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