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A novel N-alkylated prodigiosin analogue induced death in tumour cell through apoptosis or necrosis depending upon the cell type

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Abstract

Purpose

To investigate the mechanism of cell death induced by the N-alkylated prodigiosin analogue, 2,2′-[3-methoxy-1′amyl-5′-methyl-4-(1′′-pyrryl)] dipyrryl-methene (MAMPDM) in S-180 and EL-4 tumour cell lines.

Methods

Effect of MAMPDM on cell viability was assessed by MTT dye conversion. Induction of apoptosis was assessed by monitoring caspase 3 activity using a fluorogenic substrate, fragmentation of DNA by gel electrophoresis and sub-diploid DNA containing cells by flowcytometry. Necrosis was estimated by flowcytometric analysis of the uptake of propidium iodide.

Results

MAMPDM inhibited the proliferation of murine fibrosarcoma, S-180 cells and induced cell death. Investigations into the mechanism of cell death by MAMPDM in S-180 cells showed absence of hallmarks of apoptotic cell death such as activation of caspase 3, DNA fragmentation and presence of cells with sub-diploid DNA content. However, there was a rapid loss of membrane integrity as assessed by uptake of propidium iodide, which is characteristic of necrosis. In contrast to induction of necrosis in S-180 cells, MAMPDM induced apoptotic cell death in EL-4 cells as evident by activation of caspase 3, fragmentation of DNA and sub-diploid DNA containing cells.

Conclusions

MAMPDM could induce cell death by either apoptosis or necrosis depending upon the cell type. This would be of advantage in elimination of tumor cells defective in apoptotic pathway and therefore, refractory to the conventional therapies.

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References

  1. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 20:239–257

    Google Scholar 

  2. Bremer E, van Dam G, Kroesen BJ, de Leij L, Helfrich W (2006) Targeted induction of apoptosis for cancer therapy: current progress and prospects. Trends Mol Med 12:382–393

    Article  PubMed  CAS  Google Scholar 

  3. Fulda S, Debatin KM (2006) Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25:4798–4811

    Article  PubMed  CAS  Google Scholar 

  4. Papadopoulos K (2006) Targeting the Bcl-2 family in cancer therapy. Semin Oncol 33:449–456

    Article  PubMed  CAS  Google Scholar 

  5. Yamamoto C, Takemoto H, Kuno K, Yamamoto D, Tsubura A, Kamata K, Hirata H, Yamamoto A, Kano H, Seki T, Inoue K (1999) Cycloprodigiosin hydrochloride, a new H+/Cl symporter, induces apoptosis in human and rat hepatocellular cancer cell lines in vitro and inhibits the growth of hepatocellular carcinoma xenografts in nude mice. Hepatology 30:894–902

    Article  PubMed  CAS  Google Scholar 

  6. Montaner B, Navarro S, Pique M, Vilaseca M, Martinell M, Giralt E, Gil J, Perez-Tomas R (2000) Prodigiosin from the supernatant of Serratia marcescens induces apoptosis in haematopoietic cancer cell lines. Br J Pharmacol 131:585–593

    Article  PubMed  CAS  Google Scholar 

  7. Liu R, Cui CB, Duan L, Gu QQ, Zhu WM (2005) Potent in vitro anticancer activity of metacycloprodigiosin and undecylprodigiosin from a sponge-derived actinomycete Saccharopolyspora sp. nov. Arch Pharm Res 28:1341–1344

    Article  PubMed  CAS  Google Scholar 

  8. Nakashima T, Tamura T, Kurachi M, Yamaguchi K, Oda T (2005) Apoptosis-mediated cytotoxicity of prodigiosin-like red pigment produced by gamma-Proteobacterium and its multiple bioactivities. Biol Pharm Bull 28:2289–2295

    Article  PubMed  CAS  Google Scholar 

  9. Campàs C, Dalmau M, Montaner B, Barragan M, Bellosillo B, Colomer D, Pons G, Perez-Tomas R, Gil J (2003) Prodigiosin induces apoptosis of B and T cells from B-cell chronic lymphocytic leukaemia. Leukemia 17:746–750

    Article  PubMed  CAS  Google Scholar 

  10. Castillo-Avila W, Abal M, Robine S, Perez-Tomas R (2005) Non-apoptotic concentrations of prodigiosin (H+/Cl symporter) inhibit the acidification of lysosomes and induce cell cycle blockage in colon cancer cells. Life Sci 78:121–127

    Article  PubMed  CAS  Google Scholar 

  11. Pérez-Tomás R, Montaner B, Llagostera E, Soto-Cerrato V (2003) The prodigiosins, proapoptotic drugs with anticancer properties. Biochem Pharmacol 66:1447–1452

    Article  PubMed  CAS  Google Scholar 

  12. Zhang J, Shen Y, Liu J, Wei D (2005) Antimetastatic effect of prodigiosin through inhibition of tumor invasion. Biochem Pharmacol 69:407–414

    Article  PubMed  CAS  Google Scholar 

  13. Variyar PS, Chander R, Venkatachalam SR, Bongirwar DR (2002) A new red pigment from an alkalophilic Micrococcus species. Ind J Chem 14B:232–233

    Google Scholar 

  14. Pandey R, Chander R, Sainis KB (2003) A novel prodigiosin-like immunosuppressant from an alkalophilic Micrococcus sp. Int Immunopharmacol 3:159–167

    Article  PubMed  CAS  Google Scholar 

  15. Deorukhkar AA, Chander R, Ghosh SB, Sainis KB (2007) A Serratia marcescens strain producing a novel N-alkylated prodigiosin analogue. Res Microbiol (in press)

  16. Alfaro G, Lomeli C, Ocadiz R, Ortega V, Barrera R, Ramirez M, Nava G (1992) Immunologic and genetic characterization of S-180, a cell line of murine origin capable of growing in different inbred strains of mice. Vet Immunol Immunopathol 30:385–398

    Article  PubMed  CAS  Google Scholar 

  17. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  PubMed  CAS  Google Scholar 

  18. Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C (1991) A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining. J Immunol Methods 139:271–279

    Article  PubMed  CAS  Google Scholar 

  19. Troyano A, Fernández C, Sancho P, de Blas E, Aller P (2001) Effect of glutathione depletion on antitumor drug toxicity (apoptosis and necrosis) in U-937 human promonocytic cells. J Biol Chem 276:47107–47115

    Article  PubMed  CAS  Google Scholar 

  20. Hannun YA (1997) Apoptosis and dilemma of cancer chemotherapy. Blood 89:1845–1853

    PubMed  CAS  Google Scholar 

  21. Kauffmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256:42–49

    Article  CAS  Google Scholar 

  22. Leist M, Jäättelä M (2001) Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2:589–598

    Article  PubMed  CAS  Google Scholar 

  23. Okada M, Adachi S, Imai T, Watanabe K, Toyokuni S, Ueno M, Zervos AS, Kroemer G, Nakahata T (2004) A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity. Blood 103:2299–2307

    Article  PubMed  CAS  Google Scholar 

  24. Manderville RA (2001) Synthesis, proton-affinity and anti-cancer properties of the prodigiosin-group natural products. Curr Med Chem Anticancer Agents 1:195–218

    Article  PubMed  CAS  Google Scholar 

  25. Laster SM, Wood JG, Gooding LR (1988) Tumour necrosis factor can induce both apoptotic and necrotic forms of cell lysis. J Immunol 141:2629–2635

    PubMed  CAS  Google Scholar 

  26. Jänicke RU, Sprengart ML, Wati MR, Porter AG (1998) Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273:9357–9360

    Article  PubMed  Google Scholar 

  27. Soto-Cerrato V, Llagostera E, Montaner B, Scheffer GL, Perez-Tomas R (2004) Mitochondria mediated apoptosis operating irrespective of multidrug resistance in breast cancer cells by the anticancer agent prodigiosin. Biochem Pharmacol 68:1345–1352

    Article  PubMed  CAS  Google Scholar 

  28. Kitanaka C, Kuchino Y (1999) Caspase-independent programmed cell death with necrotic morphology. Cell Death Diff 6:508–515

    Article  CAS  Google Scholar 

  29. Jiang MC, Yang-Yen HF, Yen JJ, Lin JK (1996) Curcumin induces apoptosis in immortalized NIH 3T3 and malignant cancer cell lines. Nutr Cancer 26:111–120

    Article  PubMed  CAS  Google Scholar 

  30. Wang W, Guo OL, You OD, Zhang K, Yang Y, Yu J, Liu W, Zhao L, Gu HY, Hu Y, Tan Z, Wang XT (2006) The anticancer activities of wogonin in murine sarcoma S-180 both in vitro and in vivo. Biol Pharm Bull 29:1132–1137

    Article  PubMed  CAS  Google Scholar 

  31. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  PubMed  CAS  Google Scholar 

  32. Philip M, Rowley DA, Schreiber H (2004) Inflammation as a tumor promoter in cancer induction. Sem Cancer Biol 14:433–439

    Article  CAS  Google Scholar 

  33. Hirt UA, Gantner F, Leist M (2000) Phagocytosis of nonapoptotic cells dying by caspase-independent mechanisms. J Immunol 164:6520–6529

    PubMed  CAS  Google Scholar 

  34. Reiter I, Krammer B, Schwamberger G (1999) Cutting edge: differential effect of apoptotic versus necrotic tumor cells on macrophage antitumor activities. J Immunol 163:1730–1732

    PubMed  CAS  Google Scholar 

  35. Bursch W (2001) The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Diff 8:569–581

    Article  CAS  Google Scholar 

  36. Proskuryakov SY, Konoplyannikov AG, Gabai VL (2003) Necrosis: a specific form of programmed cell death? Exp Cell Res 283:1–16

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Krishna B. Sainis.

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Deorukhkar, A.A., Chander, R., Pandey, R. et al. A novel N-alkylated prodigiosin analogue induced death in tumour cell through apoptosis or necrosis depending upon the cell type. Cancer Chemother Pharmacol 61, 355–363 (2008). https://doi.org/10.1007/s00280-007-0475-y

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  • DOI: https://doi.org/10.1007/s00280-007-0475-y

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