Cancer Cell Mitochondria Targeting by Pancratistatin Analogs is Dependent on Functional Complex II and III

被引：30

作者：

Ma, Dennis ^{[1
]}

Pignanelli, Christopher ^{[1
]}

Tarade, Daniel ^{[1
]}

Gilbert, Tyler ^{[1
]}

Noel, Megan ^{[1
]}

Mansour, Fadi ^{[1
]}

Adams, Scott ^{[1
]}

Dowhayko, Alexander ^{[1
]}

Stokes, Kyle ^{[1
]}

Vshyvenko, Sergey ^{[2
,3
]}

Hudlicky, Tomas ^{[2
,3
]}

McNulty, James ^{[4
]}

Pandey, Siyaram ^{[1
]}

机构：

[1] Univ Windsor, Dept Chem & Biochem, 401 Sunset Ave, Windsor, ON N9B 3P4, Canada

[2] Brock Univ, Dept Chem, 500 Glenridge Ave, St Catharines, ON L2S 3A1, Canada

[3] Brock Univ, Ctr Biotechnol, 500 Glenridge Ave, St Catharines, ON L2S 3A1, Canada

[4] McMaster Univ, Dept Chem, 1280 Main St West, Hamilton, ON L8S 4M1, Canada

来源：

SCIENTIFIC REPORTS | 2017年 / 7卷

基金：

加拿大自然科学与工程研究理事会;

关键词：

OXIDATIVE STRESS; BREAST-CANCER; APOPTOSIS; DYSFUNCTION; CASPASE; BCL-2; MECHANISM; MODELS; GROWTH;

D O I：

10.1038/srep42957

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Enhanced mitochondrial stability and decreased dependence on oxidative phosphorylation confer an acquired resistance to apoptosis in cancer cells, but may present opportunities for therapeutic intervention. The compound pancratistatin (PST) has been shown to selectively induce apoptosis in cancer cells. However, its low availability in nature has hindered its clinical advancement. We synthesized PST analogs and a medium-throughput screen was completed. Analogs SVTH-7, -6, and -5 demonstrated potent anti-cancer activity greater than PST and several standard chemotherapeutics. They disrupted mitochondrial function, activated the intrinsic apoptotic pathway, and reduced growth of tumor xenografts in vivo. Interestingly, the pro-apoptotic effects of SVTH-7 on cancer cells and mitochondria were abrogated with

引用

页数：21

共 55 条

[1] Potential of apoptotic pathway-targeted cancer therapeutic research: Where do we stand? [J].

Baig, S. ;

Seevasant, I. ;

Mohamad, J. ;

Mukheem, A. ;

Huri, H. Z. ;

Kamarul, T. .

CELL DEATH & DISEASE, 2016, 7 :e2058-e2058

[2] Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms [J].

Belmokhtar, CA ;

Hillion, J ;

Ségal-Bendirdjian, E .

ONCOGENE, 2001, 20 (26) :3354-3362

[3] CHEMOTHERAPY Gemcitabine remains the standard of care for pancreatic cancer [J].

Berlin, Jordan ;

Benson, Al B., III .

NATURE REVIEWS CLINICAL ONCOLOGY, 2010, 7 (03) :135-137

[4] Assessing mitochondrial dysfunction in cells [J].

Brand, Martin D. ;

Nicholls, David G. .

BIOCHEMICAL JOURNAL, 2011, 435 :297-312

[5] Opinion - The role of apoptosis in cancer development and treatment response [J].

Brown, JM ;

Attardi, LD .

NATURE REVIEWS CANCER, 2005, 5 (03) :231-237

[6] Sensitization of human melanoma cells by tamoxifen to apoptosis induction by pancratistatin, a nongenotoxic natural compound [J].

Chatterjee, Sudipa June ;

McNulty, James ;

Pandey, Siyaram .

MELANOMA RESEARCH, 2011, 21 (01) :1-11

[7] Preferential killing of cancer cells with mitochondrial dysfunction by natural compounds [J].

Chen, Gang ;

Wang, Feng ;

Trachootham, Dunyaporn ;

Huang, Peng .

MITOCHONDRION, 2010, 10 (06) :614-625

[8] Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species [J].

Chen, Yongqiang ;

McMillan-Ward, Eileen ;

Kong, Jiming ;

Israels, Sara J. ;

Gibson, Spencer B. .

JOURNAL OF CELL SCIENCE, 2007, 120 (23) :4155-4166

[9] Complex I is the major site of mitochondrial superoxide production by paraquat [J].

Cocheme, Helena M. ;

Murphy, Michael P. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (04) :1786-1798

[10] Chemoenzymatic Synthesis of Amaryllidaceae Constituents and Biological Evaluation of their C-1 Analogues. The Next Generation Synthesis of 7-Deoxypancratistatin and trans-Dihydrolycoricidine [J].

Collins, Jonathan ;

Rinner, Uwe ;

Moser, Michael ;

Hudlicky, Tomas ;

Ghiviriga, Ion ;

Romero, Anntherese E. ;

Kornienko, Alexander ;

Ma, Dennis ;

Griffin, Carly ;

Pandey, Siyaram .

JOURNAL OF ORGANIC CHEMISTRY, 2010, 75 (09) :3069-3084

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