TY - JOUR
T1 - Lx2-32c, a novel taxane derivative, exerts anti-resistance activity by initiating intrinsic apoptosis pathway in vitro and inhibits the growth of resistant tumor in vivo
AU - Zhou, Qing
AU - Li, Yan
AU - Jin, Jing
AU - Lang, Liwei
AU - Zhu, Zhixiang
AU - Fang, Weishuo
AU - Chen, Xiaoguang
PY - 2012/12
Y1 - 2012/12
N2 - Resistance to anticancer drugs is a major obstacle to successful chemotherapy. Thus, the exploration of new drugs and strategies in combating resistance is of great importance. In this study, we investigated the anti-tumor drug resistance (anti-resistance for short) activity of Lx2-32c, a novel taxane, and its possible mechanisms. Lx2-32c was cytotoxic to various drug-resistant tumor cell lines, and significantly suppressed the growth of tumor xenografts in paclitaxel-resistant MX-1 nude mice. It promoted microtubule polymerization and G2/M phase arrest in MX-1/T cells. Moreover, it induced typical apoptotic characteristics indicated by morphological changes and DNA fragmentation. Apoptosis was associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c and apoptosis-inducing factor (AIF) release, elevation of the Bax/Bcl-2 ratio, activation of caspase-9,-3 but not caspase-8 and Fas/FasL, and degradation of poly(ADP-ribose) polymerase (PARP). In conclusion, Lx2-32c is an effective microtubule- stabilizing agent in overcoming paclitaxel resistance by inducing apoptosis via the intrinsic apoptotic pathway. It also displayed robust anti-paclitaxel- resistance activity in vivo. Therefore, these findings provide new insight into the strategy to overcome resistance by manipulating dysregulated apoptosis pathway.
AB - Resistance to anticancer drugs is a major obstacle to successful chemotherapy. Thus, the exploration of new drugs and strategies in combating resistance is of great importance. In this study, we investigated the anti-tumor drug resistance (anti-resistance for short) activity of Lx2-32c, a novel taxane, and its possible mechanisms. Lx2-32c was cytotoxic to various drug-resistant tumor cell lines, and significantly suppressed the growth of tumor xenografts in paclitaxel-resistant MX-1 nude mice. It promoted microtubule polymerization and G2/M phase arrest in MX-1/T cells. Moreover, it induced typical apoptotic characteristics indicated by morphological changes and DNA fragmentation. Apoptosis was associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c and apoptosis-inducing factor (AIF) release, elevation of the Bax/Bcl-2 ratio, activation of caspase-9,-3 but not caspase-8 and Fas/FasL, and degradation of poly(ADP-ribose) polymerase (PARP). In conclusion, Lx2-32c is an effective microtubule- stabilizing agent in overcoming paclitaxel resistance by inducing apoptosis via the intrinsic apoptotic pathway. It also displayed robust anti-paclitaxel- resistance activity in vivo. Therefore, these findings provide new insight into the strategy to overcome resistance by manipulating dysregulated apoptosis pathway.
KW - Anti-resistance activity
KW - Apoptosis
KW - Lx2-32c
KW - Microtubule
KW - Taxane
UR - http://www.scopus.com/inward/record.url?scp=84871558376&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871558376&partnerID=8YFLogxK
U2 - 10.1248/bpb.b12-00513
DO - 10.1248/bpb.b12-00513
M3 - Article
C2 - 23207769
AN - SCOPUS:84871558376
SN - 0918-6158
VL - 35
SP - 2170
EP - 2179
JO - Biological and Pharmaceutical Bulletin
JF - Biological and Pharmaceutical Bulletin
IS - 12
ER -