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Sulfonoquinovosyl diacylglyceride selectively targets acute lymphoblastic leukemia cells and exerts potent anti-leukemic effects in vivo.

Jain CK, Pradhan BS, Banerjee S, Mondal NB, Majumder SS, Bhattacharyya M, Chakrabarti S, Roychoudhury S, Majumder HK - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

SQDG inhibits relaxation activity of human topoisomerase I enzyme.(a) Chemical structure of Sulfonoquinovosyl Diacylglyceride (SQDG).(b) DNA relaxation assay of topo I enzyme. Supercoiled pBS DNAwas treated with topo I enzyme in the absence or presence of indicatedconcentrations of SQDG. CPT was used as control inhibitor. Lane 1,100 fmol pBS DNA; lane 2, 100 fmol pBS DNA with10 μM SQDG; lane 3, 100 fmol pBS DNAwith 50 fmol of topo I enzyme; lanes 4 to 9, same as lane 3 butin the presence of indicated concentrations of SQDG; lane 10, same as lane 3but in the presence of 5 μM CPT. Reactions wereincubated at 37 °C for 30 minutes.(c) Preincubation DNA relaxation assay. Topo I was preincubatedwith indicated concentrations of SQDG or CPT for 5 minutes andthen supercoiled pBS DNA was added. All the other conditions were same asDNA relaxation assay. (d) DNA relaxation assay of topoIIα enzyme. Lane 1, 100 fmol pBS DNA; lane 2,100 fmol pBS DNA with 50 fmol of topoIIα enzyme; lanes 3 to 5, same as lane 2 but in the presence ofindicated concentrations of SQDG. Complete scans of the different gels arepresented in the Supplementary FigureS7.
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f1: SQDG inhibits relaxation activity of human topoisomerase I enzyme.(a) Chemical structure of Sulfonoquinovosyl Diacylglyceride (SQDG).(b) DNA relaxation assay of topo I enzyme. Supercoiled pBS DNAwas treated with topo I enzyme in the absence or presence of indicatedconcentrations of SQDG. CPT was used as control inhibitor. Lane 1,100 fmol pBS DNA; lane 2, 100 fmol pBS DNA with10 μM SQDG; lane 3, 100 fmol pBS DNAwith 50 fmol of topo I enzyme; lanes 4 to 9, same as lane 3 butin the presence of indicated concentrations of SQDG; lane 10, same as lane 3but in the presence of 5 μM CPT. Reactions wereincubated at 37 °C for 30 minutes.(c) Preincubation DNA relaxation assay. Topo I was preincubatedwith indicated concentrations of SQDG or CPT for 5 minutes andthen supercoiled pBS DNA was added. All the other conditions were same asDNA relaxation assay. (d) DNA relaxation assay of topoIIα enzyme. Lane 1, 100 fmol pBS DNA; lane 2,100 fmol pBS DNA with 50 fmol of topoIIα enzyme; lanes 3 to 5, same as lane 2 but in the presence ofindicated concentrations of SQDG. Complete scans of the different gels arepresented in the Supplementary FigureS7.

Mentions: Sulfonoquinovosyl diacylglyceride (SQDG) is a member of plant sulfolipids. SQDG was firstreported in photosynthetic bacteria and higher plants by Benson and coworkers19. SQDG used in the present study was isolated by chromatographicseparation of methanolic extract of the leaves of A. indica and characterized byextensive 2D-NMR and mass spectroscopy (Fig. 1a)20.SQDG has been reported for its anti-leukemic, anti-bacterial and anti-viralactivities2021. In this study we show that SQDG inhibits topo Ienzyme of MOLT-cells, generates DNA replication stress, arrests the cells in S-phase andinduces p53 dependent apoptotic pathway. Combinations of SQDG with etoposide anddoxorubicin exert synergism and SQDG treatment reduces tumor growth in the nude micexenografted with MOLT-4 cells.


Sulfonoquinovosyl diacylglyceride selectively targets acute lymphoblastic leukemia cells and exerts potent anti-leukemic effects in vivo.

Jain CK, Pradhan BS, Banerjee S, Mondal NB, Majumder SS, Bhattacharyya M, Chakrabarti S, Roychoudhury S, Majumder HK - Sci Rep (2015)

SQDG inhibits relaxation activity of human topoisomerase I enzyme.(a) Chemical structure of Sulfonoquinovosyl Diacylglyceride (SQDG).(b) DNA relaxation assay of topo I enzyme. Supercoiled pBS DNAwas treated with topo I enzyme in the absence or presence of indicatedconcentrations of SQDG. CPT was used as control inhibitor. Lane 1,100 fmol pBS DNA; lane 2, 100 fmol pBS DNA with10 μM SQDG; lane 3, 100 fmol pBS DNAwith 50 fmol of topo I enzyme; lanes 4 to 9, same as lane 3 butin the presence of indicated concentrations of SQDG; lane 10, same as lane 3but in the presence of 5 μM CPT. Reactions wereincubated at 37 °C for 30 minutes.(c) Preincubation DNA relaxation assay. Topo I was preincubatedwith indicated concentrations of SQDG or CPT for 5 minutes andthen supercoiled pBS DNA was added. All the other conditions were same asDNA relaxation assay. (d) DNA relaxation assay of topoIIα enzyme. Lane 1, 100 fmol pBS DNA; lane 2,100 fmol pBS DNA with 50 fmol of topoIIα enzyme; lanes 3 to 5, same as lane 2 but in the presence ofindicated concentrations of SQDG. Complete scans of the different gels arepresented in the Supplementary FigureS7.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4507174&req=5

f1: SQDG inhibits relaxation activity of human topoisomerase I enzyme.(a) Chemical structure of Sulfonoquinovosyl Diacylglyceride (SQDG).(b) DNA relaxation assay of topo I enzyme. Supercoiled pBS DNAwas treated with topo I enzyme in the absence or presence of indicatedconcentrations of SQDG. CPT was used as control inhibitor. Lane 1,100 fmol pBS DNA; lane 2, 100 fmol pBS DNA with10 μM SQDG; lane 3, 100 fmol pBS DNAwith 50 fmol of topo I enzyme; lanes 4 to 9, same as lane 3 butin the presence of indicated concentrations of SQDG; lane 10, same as lane 3but in the presence of 5 μM CPT. Reactions wereincubated at 37 °C for 30 minutes.(c) Preincubation DNA relaxation assay. Topo I was preincubatedwith indicated concentrations of SQDG or CPT for 5 minutes andthen supercoiled pBS DNA was added. All the other conditions were same asDNA relaxation assay. (d) DNA relaxation assay of topoIIα enzyme. Lane 1, 100 fmol pBS DNA; lane 2,100 fmol pBS DNA with 50 fmol of topoIIα enzyme; lanes 3 to 5, same as lane 2 but in the presence ofindicated concentrations of SQDG. Complete scans of the different gels arepresented in the Supplementary FigureS7.
Mentions: Sulfonoquinovosyl diacylglyceride (SQDG) is a member of plant sulfolipids. SQDG was firstreported in photosynthetic bacteria and higher plants by Benson and coworkers19. SQDG used in the present study was isolated by chromatographicseparation of methanolic extract of the leaves of A. indica and characterized byextensive 2D-NMR and mass spectroscopy (Fig. 1a)20.SQDG has been reported for its anti-leukemic, anti-bacterial and anti-viralactivities2021. In this study we show that SQDG inhibits topo Ienzyme of MOLT-cells, generates DNA replication stress, arrests the cells in S-phase andinduces p53 dependent apoptotic pathway. Combinations of SQDG with etoposide anddoxorubicin exert synergism and SQDG treatment reduces tumor growth in the nude micexenografted with MOLT-4 cells.

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus