Shikonin circumvents cancer drug resistance by induction of a necroptotic death

Molecular Cancer Therapeutics - Tập 6 Số 5 - Trang 1641-1649 - 2007
Weidong Han1, Ling Li2, Shuang Qiu3, Qinghua Lu2, Qiangrong Pan2, Ying Gu2, Jianhong Luo3, Xun Hu2
1Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China.
21Cancer Institute, The Second Affiliated Hospital and
32Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

Tóm tắt

Abstract Defect in apoptotic signaling and up-regulation of drug transporters in cancer cells significantly limits the effectiveness of cancer chemotherapy. We propose that an agent inducing non-apoptotic cell death may overcome cancer drug resistance and showed that shikonin, a naturally occurring naphthoquinone, induced a cell death in MCF-7 and HEK293 distinct from apoptosis and characterized with (a) a morphology of necrotic cell death; (b) loss of plasma membrane integrity; (c) loss of mitochondrial membrane potentials; (d) activation of autophagy as a downstream consequence of cell death, but not a contributing factor; (e) elevation of reactive oxygen species with no critical roles contributing to cell death; and (f) that the cell death was prevented by a small molecule, necrostatin-1, that specifically prevents cells from necroptosis. The characteristics fully comply with those of necroptosis, a basic cell-death pathway recently identified by Degterev et al. with potential relevance to human pathology. Furthermore, we proved that shikonin showed a similar potency toward drug-sensitive cancer cell lines (MCF-7 and HEK293) and their drug-resistant lines overexpressing P-glycoprotein, Bcl-2, or Bcl-xL, which account for most of the clinical cancer drug resistance. To our best knowledge, this is the first report to document the induction of necroptosis by a small molecular compound to circumvent cancer drug resistance. [Mol Cancer Ther 2007;6(5):1641–9]

Từ khóa


Tài liệu tham khảo

Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol 2005;205:275–92.

Pommier Y, Sordet O, Antony S, Hayward RL, Kohn KW. Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene 2004;23:2934–49.

Simstein R, Burow M, Parker A, Weldon C, Beckman B. Apoptosis, chemoresistance, and breast cancer: insights from the MCF-7 cell model system. Exp Biol Med (Maywood) 2003;228:995–1003.

Juranka PF, Zastawny RL, Ling V. P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins. FASEB J 1989;3:2583–92.

Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 2000;92:1295–302.

Allen JD, Schinkel AH. Multidrug resistance and pharmacological protection mediated by the breast cancer resistance protein (BCRP/ABCG2). Mol Cancer Ther 2002;1:427–34.

Ruefli AA, Tainton KM, Darcy PK, Smyth MJ, Johnstone RW. P-glycoprotein inhibits caspase-8 activation but not formation of the death inducing signal complex (disc) following Fas ligation. Cell Death Differ 2002;9:1266–72.

Johnstone RW, Cretney E, Smyth MJ. P-glycoprotein protects leukemia cells against caspase-dependent, but not caspase-independent, cell death. Blood 1999;93:1075–85.

Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting P-glycoprotein. Cancer Control 2003;10:159–65.

Hersey P, Zhang XD. Overcoming resistance of cancer cells to apoptosis. J Cell Physiol 2003;196:9–18.

Stavrovskaya AA. Cellular mechanisms of multidrug resistance of tumor cells. Biochemistry (Mosc) 2000;65:95–106.

Blagosklonny MV. Prospective strategies to enforce selectively cell death in cancer cells. Oncogene 2004;23:2967–75.

Chen CH, Chern CL, Lin CC, et al. Involvement of reactive oxygen species, but not mitochondrial permeability transition in the apoptotic induction of human SK-Hep-1 hepatoma cells by shikonin. Planta Med 2003;69:1119–24.

Sankawa U, Ebizuka Y, Miyazaki T, Isomura Y, Otsuka H. Antitumor activity of shikonin and its derivatives. Chem Pharm Bull (Tokyo) 1977;25:2392–5.

Yoon Y, Kim YO, Lim NY, Jeon WK, Sung HJ. Shikonin, an ingredient of Lithospermum erythrorhizon induced apoptosis in HL60 human premyelocytic leukemia cell line. Planta Med 1999;65:532–5.

Chen X, Yang L, Oppenheim JJ, Howard MZ. Cellular pharmacology studies of shikonin derivatives. Phytother Res 2002;16:199–209.

Wu Z, Wu L, Li L, Tashiro S, Onodera S, Ikejima T. p53-mediated cell cycle arrest and apoptosis induced by shikonin via a caspase-9-dependent mechanism in human malignant melanoma A375-2 cells. J Pharmacol Sci 2004;94:166–76.

Wu Z, Wu LJ, Li LH, Tashiro S, Onodera S, Ikejima T. Shikonin regulates HeLa cell death via caspase-3 activation and blockage of DNA synthesis. J Asian Nat Prod Res 2004;6:155–66.

Degterev A, Huang Z, Boyce M, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 2005;1:112–9.

Godard T, Deslandes E, Lebailly P, et al. Comet assay and DNA flow cytometry analysis of staurosporine-induced apoptosis. Cytometry 1999;36:117–22.

Arnoult D, Parone P, Martinou JC, Antonsson B, Estaquier J, Ameisen JC. Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli. J Cell Biol 2002;159:923–9.

Cregan SP, Dawson VL, Slack RS. Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 2004;23:2785–96.

Kagawa S, Gu J, Honda T, et al. Deficiency of caspase-3 in MCF7 cells blocks Bax-mediated nuclear fragmentation but not cell death. Clin Cancer Res 2001;7:1474–80.

Benjamin CW, Hiebsch RR, Jones DA. Caspase activation in MCF7 cells responding to etoposide treatment. Mol Pharmacol 1998;53:446–50.

Hansen TM, Smith DJ, Nagley P. Smac/DIABLO is not released from mitochondria during apoptotic signalling in cells deficient in cytochrome c. Cell Death Differ 2006;13:1181–90.

Murphy KM, Ranganathan V, Farnsworth ML, Kavallaris M, Lock RB. Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells. Cell Death Differ 2000;7:102–11.

Pan Q, Lu Q, Zhang K, Hu X. Dibenzocyclooctadiene lingnans: a class of novel inhibitors of P-glycoprotein. Cancer Chemother Pharmacol 2006;58:99–106.

Qiangrong P, Wang T, Lu Q, Hu X. Schisandrin B-a novel inhibitor of P-glycoprotein. Biochem Biophys Res Commun 2005;335:406–11.

Suarez Y, Gonzalez L, Cuadrado A, Berciano M, Lafarga M, Munoz A. Kahalalide F, a new marine-derived compound, induces oncosis in human prostate and breast cancer cells. Mol Cancer Ther 2003;2:863–72.

Ribas J, Bettayeb K, Ferandin Y, et al. 7-Bromoindirubin-3′-oxime induces caspase-independent cell death. Oncogene 2006;25:6304–18.

Ruefli AA, Smyth MJ, Johnstone RW. HMBA induces activation of a caspase-independent cell death pathway to overcome P-glycoprotein-mediated multidrug resistance. Blood 2000;95:2378–85.

Ruefli AA, Bernhard D, Tainton KM, Kofler R, Smyth MJ, Johnstone RW. Suberoylanilide hydroxamic acid (SAHA) overcomes multidrug resistance and induces cell death in P-glycoprotein-expressing cells. Int J Cancer 2002;99:292–8.

Johnson WW. P-glycoprotein-mediated efflux as a major factor in the variance of absorption and distribution of drugs: modulation of chemotherapy resistance. Methods Find Exp Clin Pharmacol 2002;24:501–14.

Bakker M, Renes J, Groenhuijzen A, et al. Mechanisms for high methoxymorpholino doxorubicin cytotoxicity in doxorubicin-resistant tumor cell lines. Int J Cancer 1997;73:362–6.

Marcus AI, Peters U, Thomas SL, et al. Mitotic kinesin inhibitors induce mitotic arrest and cell death in Taxol-resistant and -sensitive cancer cells. J Biol Chem 2005;280:11569–77.

Guo XP, Zhang XY, Zhang SD. [Clinical trial on the effects of shikonin mixture on later stage lung cancer]. Zhong Xi Yi Jie He Za Zhi 1991;11:598–9.

Yu L, Alva A, Su H, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004;304:1500–2.

Thông tin
Thông tin xuất bản

Molecular Cancer Therapeutics

Tập 6 Số 5

1641-1649

Thông tin tác giả