Chamaejasmin B exerts anti-MDR effect in vitro and in vivo via initiating mitochondria-dependant intrinsic apoptosis pathway

Abstract

Multidrug resistance (MDR) is the main obstacle limiting the efficacy of cancer chemotherapy. Looking for novel anti-MDR agents is an important way to conquer cancer drug resistance. We recently established that chamaejasmin B (CHB), a natural biflavone from Stellera chamaejasme L., is the major active component. However, its anti-MDR activity is still unknown. This study investigated the anti-MDR effect of CHB and the underlying mechanisms. First, it was found that CHB inhibited the growth of both sensitive and resistant cell lines in vitro, and the average resistant factor (RF) of CHB was only 1.26. Furthermore, CHB also displayed favorable anti-MDR activity in KB and KBV200 cancer cells xenograft mice. Subsequent study showed that CHB induced G0/G1 cell cycle arrest as well as apoptosis both in KB and in resistant KBV200 cancer cells. Further studies showed that CHB had no influence on the level of Fas/FasL and activation of procaspase 8. However, CHB-induced apoptosis was dependent on the activation of caspase 9 and caspase 3. Moreover, CHB treatment resulted in the elevation of the Bax/Bcl-2 ratio, attenuation of mitochondrial membrane potential (ΔΨm), and release of cytochrome c and apoptosis-inducing factor from mitochondria into cytoplasm both in KB and KBV200 cells. In conclusion, CHB exhibited good anti-MDR activity in vitro and in vivo, and the underlying mechanisms may be related to the activation of mitochondrial-dependant intrinsic apoptosis pathway. These findings provide a new leading compound for MDR therapy and supply a new evidence for the potential of CHB to be employed in clinical trial of MDR therapy in cancers.