Effects of geranyl-phloroacetophenone on the induction of apoptosis and chemosensitization of adriamycin-resistant MCF-7 human breast cancer cells
- Effects of geranyl-phloroacetophenone on the induction of apoptosis and chemosensitization of adriamycin-resistant MCF-7 human breast cancer cells
- 김정애; 조미연; 박수영; 박수민; 이용록; 곽미경[곽미경]
- GLUTATHIONE-S-TRANSFERASE; MULTIDRUG-RESISTANCE; DRUG-RESISTANCE; DOWN-REGULATION; P-GLYCOPROTEIN; BCL-2 EXPRESSION; TUMOR-CELLS; IN-VIVO; P53; BAX
- Issue Date
- PHARMACEUTICAL SOC KOREA
- ARCHIVES OF PHARMACAL RESEARCH, v.35, no.5, pp.911 - 919
- Polyphenols are known to induce apoptosis in many cancer cells and are proposed to be promising modulators of drug resistance. In the present study, we report that 3-geranyl-phloroacetophenone (3-GAP), a synthetic polyphenol, induces apoptosis and modulates drug resistance. In adriamycin-resistant MCF-7 human breast cancer (MCF-7/ADR) cells, which express a mutant form of p53, 3-GAP induced significant apoptosis, which was accompanied by no change in p53 transcriptional activity, but an increase in Bax expression, cyt c release, and activation of caspase-9, 7, and 3. In addition, 3-GAP significantly decreased the activity and expression level of glutathione S-transferase pi (GST pi), a factor that induces drug resistance. Along with GST pi inhibition, 3-GAP also induced a marked depletion of GSH, an endogenous antioxidant. The GST-inhibitory activity of 3-GAP correlated with the sensitization of MCF-7/ADR cells to doxorubicin. Under serum withdrawal conditions, the JNK inhibitor SP600125 significantly decreased the viability of the parent MCF-7 cells but not of MCF-7/ADR cells. In addition, the viability of 3-GAP-treated MCF-7/ADR cells was similar to those of MCF-7 cells treated with SP600125 alone or MCF-7/ADR cells co-treated with SP600125 and 3-GAP. These results indicate that JNK activity in MCF-7/ADR cells is halted by high levels of GST pi, and that 3-GAP releases JNK from GST pi's inhibition. In conclusion, 3-GAP induces apoptosis in and sensitizes drug-resistant MCF-7/ADR cells. These effects are mediated through p53-independent caspase-3 activation and reduction of the capacity for cellular antioxidants, such as GST pi and GSH.
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