Effects of geranyl-phloroacetophenone on the induction of apoptosis and chemosensitization of adriamycin-resistant MCF-7 human breast cancer cells.
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 (GSTπ), a factor that induces drug resistance. Along with GSTπ 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 GSTπ, and that 3-GAP releases JNK from GSTπ'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 GSTπ and GSH.
College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
Mi-Yeon
MY
Cho
Su-Young
SY
Park
Sumin
S
Park
Yong Rok
YR
Lee
Mi-Kyoung
MK
Kwak
Jung-Ae
JA
Kim
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D011753:Pyrones / Q000494:pharmacology* / Q000627:therapeutic use; D013729:Terpenes / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
C454562:3-geranyl-4-hydroxy-6-(2-hydroxypropyl)-2-pyrone; D011753:Pyrones; D013729:Terpenes; D004317:Doxorubicin