Metformin and epithelial ovarian cancer therapeutics.
BACKGROUND
Ovarian cancer is one of the most common lethal gynecological malignancies world-wide. Despite an initial 70-80% response rate, most patients relapse within 1-2 years and develop chemo-resistance. Hence, the identification of novel drugs or the repositioning of known drugs to re-sensitize ovarian cancer cells to existing chemotherapy regimens is needed. Here, we evaluated the effect of metformin (an anti-diabetic drug) on ovarian cancer cells, based on its putative effect on other solid tumors.


METHODS
Primary cultures of epithelial ovarian cancer cells established from ascitic fluids of untreated ovarian cancer patients and the SKOV-3 ovarian cancer-derived cell line were used. The respective cells were treated with metformin, carboplatin and paclitaxel alone and its various combinations and their effects, including the ability to induce apoptosis, were examined. Concomitantly, the cells were assessed for the expression of several apoptosis-related mRNAs and proteins using quantitative real time PCR, flowcytometry and Western blotting.


RESULTS
We found that metformin induced apoptosis in the ovarian cancer cells tested, and provoked a cell cycle arrest in the G0/G1 and S-phase. Metformin induced apoptosis by down-regulating Bcl-2 and Bcl-xL expression, and up-regulating Bax and Cytochrome c expression. We also found that the apoptosis induction by metformin could be enhanced by a combinatorial use of carboplatin and/or paclitaxel.


CONCLUSIONS
Our data indicate that metformin can induce apoptosis in both primary ovarian cancer cells and in SKOV-3 cells. When metformin was combined with carboplatin or paclitaxel, an increased apoptotic activity was observed, implicating a chemo-adjuvant potential.
Department of Biochemistry, All India Institute of Medical Science (AIIMS), Room no 3027A, Ansari Nagar, New Delhi, 110029, India.
Seema
S
Patel
Institute of Rotary and Cancer Hospital (IRCH), AIIMS, New Delhi, India.
Lalit
L
Kumar
Department of Biochemistry, All India Institute of Medical Science (AIIMS), Room no 3027A, Ansari Nagar, New Delhi, 110029, India. singh_neeta26@rediffmail.com.
Neeta
N
Singh
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D016190:Carboplatin / Q000494:pharmacology*; D000077216:Carcinoma, Ovarian Epithelial; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D007004:Hypoglycemic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D008687:Metformin; D016190:Carboplatin; D017239:Paclitaxel
Apoptosis; Bcl-2; Metformin; Ovarian cancer