title: Sulfonoquinovosyl diacylglyceride selectively targets acute lymphoblastic leukemia cells and exerts potent anti-leukemic effects in vivo.
abstract: DNA topoisomerase II inhibitors e.g. doxorubicin and etoposide are currently used in the chemotherapy for acute lymphoblastic leukemia (ALL). These inhibitors have serious side effects during the chemotherapy e.g. cardiotoxicity and secondary malignancies. In this study we show that sulfonoquinovosyl diacylglyceride (SQDG) isolated from Azadirachta indica exerts potent anti-ALL activity both in vitro and in vivo in nude mice and it synergizes with doxorubicin and etoposide. SQDG selectively targets ALL MOLT-4 cells by inhibiting catalytic activity of topoisomerase I enzyme and inducing p53 dependent apoptotic pathway. SQDG treatment induces recruitment of ATR at chromatin and arrests the cells in S-phase. Down-regulation of topoisomerase I or p53 renders the cells less sensitive for SQDG, while ectopic expression of wild type p53 protein in p53 deficient K562 cells results in chemosensitization of the cells for SQDG. We also show that constant ratio combinations of SQDG and etoposide or SDQG and doxorubicin exert synergistic effects on MOLT-4 cell killing. This study suggests that doses of etoposide/doxorubicin can be substantially reduced by combining SQDG with these agents during ALL chemotherapy and side effects caused can be minimized. Thus dual targeting of topoisomerase I and II enzymes is a promising strategy for improving ALL chemotherapy.
authors.affiliation: 1] Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India [2] Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.
authors.forename: Chetan Kumar
authors.initials: CK
authors.lastname: Jain
authors.affiliation: Division of Embryo Biotechnology, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: Bhola Shankar
authors.initials: BS
authors.lastname: Pradhan
authors.affiliation: Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.
authors.forename: Sukdeb
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.
authors.forename: Nirup Bikash
authors.initials: NB
authors.lastname: Mondal
authors.affiliation: Division of Embryo Biotechnology, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: Subeer S
authors.initials: SS
authors.lastname: Majumder
authors.affiliation: Structural Biology and Bioinformatics Division. CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.
authors.forename: Madhumita
authors.initials: M
authors.lastname: Bhattacharyya
authors.affiliation: Structural Biology and Bioinformatics Division. CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.
authors.forename: Saikat
authors.initials: S
authors.lastname: Chakrabarti
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
authors.affiliation: Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, India.
authors.forename: Hemanta Kumar
authors.initials: HK
authors.lastname: Majumder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006017:Glycolipids / Q000494:pharmacology*; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D015398:Signal Transduction / Q000187:drug effects; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006017:Glycolipids; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53; C013694:sulfoquinovosyl diglyceride; D005047:Etoposide; D004317:Doxorubicin