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.
Highlights
Used in combination with other anti-Acute lymphoblastic leukemia (ALL) agents during remission induction and consolidation phases of the chemotherapy, respectively
This study demonstrates that Sulfonoquinovosyl diacylglyceride (SQDG) isolated from the leaves of Azadirachta indica exerts selective and potent anti-ALL effects by inhibiting DNA relaxation activity of topoisomerase I (topo I)
One difference among MOLT-4, MOLT-3, Reh and the other leukemic cells used in this study is p53 status. p53 is well known for inducing cell cycle arrest and/or apoptosis in response to various cellular stresses[49] and p53 is activated upon genotoxic stresses like DNA damage and DNA replication stress[50,51]
Summary
Used in combination with other anti-ALL agents during remission induction and consolidation phases of the chemotherapy, respectively. Enzymatic reaction cycle of topo I proceeds through four different steps- (a) DNA binding: the enzyme binds on its preferential binding site, (b) DNA nicking: nucleophilic attack on phosphodiester backbone by the active site tyrosine-723 residue and formation of transient 3′ phosphotyrosyl bond, (c) controlled strand rotation and (d) religation of DNA strand. Trapping of the enzyme and DNA in nicked condition by topo inhibitors i.e. stabilization of covalent enzyme-DNA complexes, generates DNA lesions, initiates cell cycle arrest and induces apoptosis. In this study we show that SQDG inhibits topo I enzyme of MOLT-cells, generates DNA replication stress, arrests the cells in S-phase and induces p53 dependent apoptotic pathway. Combinations of SQDG with etoposide and doxorubicin exert synergism and SQDG treatment reduces tumor growth in the nude mice xenografted with MOLT-4 cells
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