Methyl-beta-cyclodextrin enhances the susceptibility of human breast cancer cells to carboplatin and 5-fluorouracil: involvement of Akt, NF-kappaB and Bcl-2.
The response rates of extensively used chemotherapeutic drugs, carboplatin (Carb) or 5-fluorouracil (5-FU) are relatively disappointing because of considerable side effects associated with their high-dose regimen. In the present study, we determined whether treatment with a cholesterol depleting agent, methyl-beta-cyclodextrin (MCD), enhances the weak efficacy of low doses of Carb or 5-FU in human breast cancer cells. Data demonstrate that pretreatment with MCD significantly potentiates the cytotoxic activity of Carb and 5-FU in both MCF-7 and MDA-MB-231. Furthermore, we explored the molecular basis of enhanced cytotoxicity, and our data revealed that low-dose treatment with these drugs in MCD pretreated cells exhibited significantly decreased Akt phosphorylation, NF-kappaB activity and down-regulation in expression of anti-apoptotic protein Bcl-2. In addition, MCD pretreated cells demonstrated an increased intracellular drug accumulation as compared to cells treated with drugs alone. Taken together, our data provide the basis for potential therapeutic application of MCD in combination with other conventional cytotoxic drugs to facilitate reduction of drug dosage that offers a better chemotherapeutic approach with low toxicity.
Upadhyay
Ankur Kumar
AK
National Centre for Cell Science, NCCS Complex, Ganeshkhind, Pune-411007, India.
Singh
Sandeep
S
Chhipa
Rishi Raj
RR
Vijayakumar
Maleppillil Vavachan
MV
Ajay
Amrendra Kumar
AK
Bhat
Manoj Kumar
MK
D000277:Adjuvants, Pharmaceutic / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016190:Carboplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000493:pharmacokinetics / Q000494:pharmacology*
D000277:Adjuvants, Pharmaceutic; D000970:Antineoplastic Agents; D004338:Drug Combinations; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D016190:Carboplatin; D051058:Oncogene Protein v-akt; D005472:Fluorouracil