Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epothilones are a new class of natural products that bind to tubulin and prevent the depolymerization of microtubules, although they have no structural similarity to paclitaxel. Taxanes are only marginally effective in the treatment of disseminated prostate cancer, although they may have useful activity when administered in combination with estramustine. Unlike paclitaxel, epothilones are not substrates for P-glycoprotein and are active in multidrug resistant cells. Epothilones A and B (EA, EB) have recently been synthesized in toto. In this report, we examine the effects of synthetic epothilones and their desoxy derivatives, as well as paclitaxel, on prostate cancer cell lines. EB was the most active of these compounds in tissue culture (IC(50): 50-75 pM), four to ten-fold more potent than paclitaxel. EA and the desoxyderivatives of EA and EB (dEA, dEB) were also active, but less potent than EB. Each of these compounds causes mitotic block followed by apoptotic cell death. The relative potencies for cell cycle arrest and cytotoxicity directly correlate with the ability of the drugs to bind microtubules, stabilize mitotic spindles and induce the formation of interphase microtubule bundles. Therefore, synthetic epothilones are potent inhibitors of prostate cancer cell lines and work in a fashion similar to paclitaxel. Recently, we showed that farnesyl transferase inhibitors sensitize tumor cells to paclitaxel-induced mitotic arrest. We now have extended these observations to show that paclitaxel and the epothilones synergize with FTI to arrest the growth of prostate cancer cells. Moreover, this occurs in DU145, a cell line that is not particularly sensitive to the FTI. The combination of FTI and epothilone represent a new potential clinical strategy for the treatment of advanced prostatic cancer.
Prostate Cancer Prostatic Dis 1999 Jan
PMID:The microtubule-stabilizing agents epothilones A and B and their desoxy-derivatives induce mitotic arrest and apoptosis in human prostate cancer cells. 1249 65

Multidrug resistant prostate cancer cell lines DU 0.03 and PC 0.03 were established from the parental prostate cancer cell lines DU145 and PC-3 respectively by stepwise selection in doxorubicin (DOX) from 0.001 to 0.03 &mgr;g/ml. As cells adapted to each concentration of DOX. the drug concentration was increased by 0.001 &mgr;g/ml. The chemosensitivity of each line was determined by growth inhibition assay. The DU 0.03 and PC 0.03 lines exhibit a 5-10-fold and 1.3-2.8-fold increase in resistance to anthracyclines, vinblastine (VLB) and mitozantrone (Mito), respectively. Verapamil (5 &mgr;M) partially reversed the resistance to the anthracycline and completely reversed the resistance to VLB and Mito. Drug kinetic studies measured by intracellular accumulation of (3)H-daunorubicin demonstrated a 3 fold decrease in the level of intracellular (3)H-daunorubicin in the PC 0.03 and DU 0.03 resistant lines compared with their respective parental line. This effect was partially reversed by 5 &mgr;M verapamil. The expression of MDR1 and MRP genes was analysed by Northern blotting and RT-PCR. P-glycoprotein (Pgp) and MRP protein were tested by immunocytochemistry staining using the monoclonal antibodies J-SB1. C219 and MRK16 (Pgp) and MRPm6 and MRPr1 (MRP). Neither Northern blot analysis nor the more sensitive RT-PCR demonstrated detectable MDR1 transcripts in any of the prostate cancer cell lines and the three Pgp monoclonal antibodies failed to reveal expression of Pgp. A 2-4-fold increase in MRP1 mRNA levels in the drug resistant DU 0.03 and PC 0.03 lines were demonstrated by both Northern blotting and RT-PCR consistent with the findings observed after staining by the two specific monoclonal antibodies, MRPm6 and MRPr1. Southern blot analysis demonstrated a 2-fold increase in the MRP1 gene copy number in the PC 0.03 line but not in the DU 0.03 line, suggesting that the overexpression of the MRP gene was regulated at the level of transcription in the latter line. We conclude that MRP1 not MDR1 overexpression. contributes to acquired drug resistance in these two prostate cancer cell lines. Prostate Cancer and Prostatic Diseases (2000) 3, 66-75
Prostate Cancer Prostatic Dis 2000 Aug
PMID:MRP1 not MDR1 gene expression is the predominant mechanism of acquired multidrug resistance in two prostate carcinoma cell lines. 1249 2