Overcoming chemoresistance in prostate cancer with Chinese medicine Tripterygium wilfordii via multiple mechanisms

Abstract

A leading cause of cancer chemotherapy failure is chemoresistance, which often involves multiple mechanisms. Chinese medicines (CM) usually contain multiple components which could potentially target many mechanisms simultaneously and may offer an advantage over single compounds that target one mechanism at a time. The purpose of this study was to investigate the chemosensitizing effect (CE) of a specific CM, Tripterygium wilfordii (TW), on prostate cancer cells resistant to docetaxel (Dtx) and identify the potential mechanisms. The CE of TW (in combination with Dtx) was evaluated in two Dtx resistant prostate cancer cell lines (PC3-TxR and DU145-TxR) and the efficacy of the combination for resistant PC3-TxR tumor was investigated using a xenograft mouse model. For mechanistic study, the inhibitory effect of TW on P-glycoprotein activity was assessed. In addition, novel gene targets of TW were identified using DNA microarray and quantitative PCR. Results showed that TW induced a CE of 8 and >38 folds in PC3-TxR and DU145-TxR cells, respectively with Dtx IC50 reversed back to that of the sensitive parent cells. An optimum dose of TW+Dtx significantly retarded tumor growth in mice compared to TW or Dtx alone. TW inhibited P-glycoprotein activity and induced a significant gene expression changes in genes related to angiogenesis, cell cycle regulation and differentiation. Our in vitro and in vivo studies demonstrate that TW in combination with Dtx was able to overcome the chemoresistance and suppress resistant prostate tumor growth via multi-mechanisms.

Enhanced anti-tumor efficacy and mechanisms associated with docetaxel-piperine combination-in vitroandin vivoinvestigation using a taxane-resistant prostate cancer model

“…Thus, careful in vivo efficacy with mechanistic study and concentration determination of the relevant compounds are important. In addition, the dose of DTX was chosen based on literature reports [ 17 , 54 ]. With regard to the dose of PIP, we firstly tried 100 mg/kg, the same dose as Makhov’s study in which PIP was used as a chemosensitizer to DTX [ 37 ].…”

“…Moreover, a synthesized naphthoflavone as CYP1B1 inhibitor could decrease the IC 50 of DTX in MCF7/1B1 cells [ 16 ]. Although Tripterygium wilfordii is attractive in combination DTX for potential mCRPC resistant to DTX, Tripterygium wilfordii as an extract has problem of quality control and therapeutic monitoring [ 17 ]. Therefore, a single natural compound which can overcome DTX resistance will be more attractive.…”

Demethylzeylasteral inhibits glioma growth by regulating the miR-30e-5p/MYBL2 axis

“…Many studies have shown that the active ingredient extracts of TwHF also exhibit anti-tumour activities. Wang Z and colleagues found that TwHF seems to be able to sensitise resistant prostate cancer cells to the chemotherapeutic effect of docetaxel 14 .…”

Genetic Transformation System for Woody Plant Tripterygium wilfordii and Its Application to Product Natural Celastrol

“… Yang et al (2006) showed that celastrol is an effective natural protease inhibitor that induces prostate cancer cell apoptosis ( Li-Weber, 2013 ). A series of subsequent studies showed that celastrol exhibits pharmaceutical activities, such as anti-tumor, anti-rheumatism, analgesia activities ( Ríos, 2010 ; Kannaiyan et al, 2011 ; Wang et al, 2016 ). Moreover, there have been reported that celastrol is a leptin sensitizer and a promising agent for the pharmacological treatment of obesity ( Greenhill, 2015 ; Liu et al, 2015 ; Ma et al, 2015 ).…”