title: Strategy to enhance efficacy of doxorubicin in solid tumor cells by methyl-β-cyclodextrin: Involvement of p53 and Fas receptor ligand complex.
abstract: Doxorubicin (DOX) is one of the preferred drugs for treating breast and liver cancers. However, its clinical application is limited due to severe side effects and the accompanying drug resistance. In this context, we investigated the effect on therapeutic efficacy of DOX by cholesterol depleting agent methyl-β-cyclodextrin (MCD), and explored the involvement of p53. MCD sensitizes MCF-7 and Hepa1-6 cells to DOX, Combination of MCD and marginal dose of DOX reduces the cell viability, and promoted apoptosis through induction of pro-apoptotic protein, Bax, activation of caspase-8 and caspase-7, down regulation of anti-apoptotic protein Bcl-2 and finally promoting PARP cleavage. Mechanistically, sensitization to DOX by MCD was due to the induction of FasR/FasL pathway through p53 activation. Furthermore, inhibition of p53 by pharmacological inhibitor pifithrin-α (PFT-α) or its specific siRNA attenuated p53 function and down-regulated FasR/FasL, thereby preventing cell death. Animal experiments were performed using C57BL/6J mouse isografted with Hepa1-6 cells. Tumor growth was retarded and survival increased in mice administered MCD together with DOX to as compared to either agent alone. Collectively, these results suggest that MCD enhances the sensitivity to DOX for which wild type p53 is an important determinant.
authors.affiliation: National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune- 411007, India.
authors.forename: Naoshad
authors.initials: N
authors.lastname: Mohammad
authors.affiliation: National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune- 411007, India.
authors.forename: Shivendra Vikram
authors.initials: SV
authors.lastname: Singh
authors.affiliation: National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune- 411007, India.
authors.forename: Parmanand
authors.initials: P
authors.lastname: Malvi
authors.affiliation: National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune- 411007, India.
authors.forename: Balkrishna
authors.initials: B
authors.lastname: Chaube
authors.affiliation: National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune- 411007, India.
authors.forename: Dipti
authors.initials: D
authors.lastname: Athavale
authors.affiliation: Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham University, Kollam-690525, India.
authors.forename: Muralidharan
authors.initials: M
authors.lastname: Vanuopadath
authors.affiliation: Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham University, Kollam-690525, India.
authors.forename: Sudarslal Sadasivan
authors.initials: SS
authors.lastname: Nair
authors.affiliation: Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham University, Kollam-690525, India.
authors.forename: Bipin
authors.initials: B
authors.lastname: Nair
authors.affiliation: National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune- 411007, India.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Bhat
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015996:Survival Rate; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000737:chemistry*; D019014:fas Receptor / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D053222:Fas Ligand Protein; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D047392:beta-Cyclodextrins; D019014:fas Receptor; C108732:methyl-beta-cyclodextrin; D004317:Doxorubicin