Lupeol triterpene, a novel diet-based microtubule targeting agent: Disrupts survivin/cFLIP activation in prostate cancer cells

Abstract

Recently we showed Lupeol, a triterpene, found in fruits and vegetables inhibits the growth of tumors originated from human androgen-sensitive prostate cancer (CaP) cells and decreases the serum-PSA levels in a mouse model. Here, we provide evidence that Lupeol inhibits the growth of androgensensitive as well as androgen-insensitive CaP cells by inducing G2/M cell cycle arrest without exhibiting any toxicity to normal human prostate epithelial cells (PrEC) at the doses at which it kills cancer cells. We observed that Lupeol treatment to LNCaP and DU145 cells resulted in a dose dependent (i) decrease in the protein levels of Cyclins-A, -B1, -D1, -D2, -E2, cyclin-dependent kinase (cdk)-2 and (ii) increase in the protein level of CDK-inhibitor p21. Since G2/M cell cycle phase is regulated by microtubule assembly, we investigated effect of Lupeol on microtubule assembly, its regulation and down-stream targets in CaP cells. Lupeol treatment significantly modulated the level of (i) microtubule components α-tubulin and β-tubulin, (ii) microtubule-regulatory protein stathmin, and (iii) microtubule-regulatory downstream target/pro-survival protein survivin. Lupeol treatment also decreased the level of anti-apoptotic protein cFLIP. Finally, Lupeol was observed to significantly decrease the transcriptional activation of Survivin and cFLIP genes in CaP cells. We conclude that the Lupeol-induced growth inhibition of CaP cells is a net outcome of simultaneous effects on Stathmin, cFLIP, and Survivin which results in the disruption of microtubule assembly. We suggest that Lupeol alone or as an adjuvant to other microtubule agents could be developed as a potential agent for the treatment of human CaP.

Anti-inflammatory effects and possible mechanism of action of lupeol acetate isolated from Himatanthus drasticus (Mart.) Plumel

“…It is accepted that the anti-inflammatory property of lupeol often accompany its immune modulatory and anti-tumor action [29,30,4,15]. Despite the wealth literature data on lupeol, there are very few reports on lupeol acetate.…”

Epicatechin‐rich cocoa polyphenol inhibits Kras‐activated pancreatic ductal carcinoma cell growth in vitro and in a mouse model

“…Cells (60% confluent) were starved for 12 hr to arrest them in G0 phase of the cell cycle, after which they were treated with CP (0.025%) and epicatechin (0.025%) in complete media for 48 hr. The harvested cells were processed for cell‐cycle analysis as described earlier 23…”

Identification of Novel Anti-inflammatory Agents from Ayurvedic Medicine for Prevention of Chronic Diseases: “Reverse Pharmacology” and “Bedside to Bench” Approach

“…The mango contains a triterpene called lupeol which shows strong anti-cancer activity by disrupting survivin/cFLIP activation, modulation of expression levels of cyclins-A, -B1, -D1, -D2, -E2, cyclin-dependent kinase (cdk)-2, CDK-inhibitor p21 and finally inducing G2/M cell cycle arrest [190]. Mangiferin, a xanthone glucoside, isolated from the leaves of Mangifera indica possesses significant antidiabetic, antihyperlipidemic and antiatherogenic properties [191].…”