Abstract
Apoptotic resistance is the main obstacle for treating cancer patients with chemotherapeutic drugs. Multidrug resistance (MDR) is often characterized by the expression of P-glycoprotein (P-gp), a 170-KD ATP-dependent drug efflux protein. Functional P-gp can confer resistance to activate caspase-8 and -3 dependent apoptosis induced by a range of different stimuli, including tumor necrosis and chemotherapeutic drugs such as docetaxel and vincristine. We demonstrated here that comparison of sensitive KB cells, P-gp positive (P-gp+ve) KBv200 cells were extremely resistant to apoptosis induced by docetaxel. FG020326, a pharmacological inhibitor of P-gp function, could enhance concentration-dependently the effect of docetaxel on cell apoptosis and sensitize caspase-8, -9 and -3 activation in P-gp overexpressing KBv200 cells, but not in KB cells. Therefore, the enhancement of caspase-8, -9 and -3 activation induced by docetaxel may be one of the key mechanisms of the reversal of P-gp mediated docetaxel resistance by FG020326.
Highlights
Docetaxel (Taxotere, TXT), a semisynthetic antineoplastic agent that is very similar to paclitaxel in structure, mechanism of action, and spectrum of antitumor activity, differing structurally from paclitaxel at the C-10 position where docetaxel has a hydroxy group instead of an acetyl group and contains an OC(CH3)3 moiety on the C-13 side chain as opposed to a benzamide phenyl group as in paclitaxel, has significant antitumor activity in a number of human cancers, including advanced ovarian, breast and non-small cell lung carcinomas
Multidrug resistance mediated by the drug efflux protein, P-glycoprotein (P-gp), is one of the mechanisms that tumor cells use to escape death induced by chemotherapeutic agents such as paclitaxel and docetaxel
To investigate whether FG020326 could reverse the apoptotic resistance to docetaxel and whether it is involved in apoptotic mechanisms, DNA fragmentation and the pathway of apoptosis induced by docetaxel were studied in the presence or absence of FG020326 in P-gp positive (P-gp+ve) KBv200 cells and their parental P-gp negative (P-gp−ve) sensitive KB cells
Summary
Docetaxel (Taxotere, TXT), a semisynthetic antineoplastic agent that is very similar to paclitaxel in structure, mechanism of action, and spectrum of antitumor activity, differing structurally from paclitaxel at the C-10 position where docetaxel has a hydroxy group instead of an acetyl group and contains an OC(CH3) moiety on the C-13 side chain as opposed to a benzamide phenyl group as in paclitaxel, has significant antitumor activity in a number of human cancers, including advanced ovarian, breast and non-small cell lung carcinomas. Multidrug resistance mediated by the drug efflux protein, P-glycoprotein (P-gp), is one of the mechanisms that tumor cells use to escape death induced by chemotherapeutic agents such as paclitaxel and docetaxel. Johnstone et al [16] demonstrated that functional P-gp inhibited activation of caspase -8 and -3 following Fas ligation and this inhibitory effect could be reversed by inhibiting P-gp, such as using specific anti-P-gp monoclonal antibodies (mAbs). Many chemotherapeutic drugs, such as doxorubicin and vincristine, induced cell apoptosis in a receptor-dependent manner [15,16,18,19]. To investigate whether FG020326 could reverse the apoptotic resistance to docetaxel and whether it is involved in apoptotic mechanisms, DNA fragmentation and the pathway of apoptosis induced by docetaxel were studied in the presence or absence of FG020326 in P-gp+ve KBv200 cells and their parental P-gp−ve sensitive KB cells
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