Novel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells

Overcoming platinum drug resistance represents a major clinical challenge in cancer treatment. We discovered a novel drug combination using cisplatin and a class of thioquinazolinone derivatives including mdivi-1 (mitochondrial division inhibitor-1), that induces synergistic apoptosis in platinum resistant tumor cells, including those from cisplatin-refractory endstage ovarian cancer patients. However, through study of the combination effect on Drp1 (the reported target of mdivi-1) knockout MEF cells and the functional analysis of mdivi-1 analogs, we revealed that the synergism between mdivi-1 and cisplatin is Drp1-independent. Mdivi-1 impairs DNA replication and its combination with cisplatin induces a synergistic increase of replication stress and DNA damage, causing a preferential upregulation of a BH3-only protein Noxa. Mdivi-1 also represses mitochondrial respiration independent of Drp1, and the combination of mdivi-1 and cisplatin triggers substantial mitochondrial uncoupling and swelling. Upregulation of Noxa and simultaneous mitochondrial swelling causes synergistic induction of mitochondrial outer membrane permeabilization (MOMP), proceeding robust mitochondrial apoptotic signaling independent of Bax/Bak. Thus, the novel mode of MOMP induction by the combination through the “dual-targeting” potential of mdivi-1 on DNA replication and mitochondrial respiration suggests a novel class of compounds for platinum-based combination option in the treatment of platinum as well as multidrug resistant tumors.

[1]  Richard G. Moore,et al.  A prospective study evaluating the clinical relevance of a chemoresponse assay for treatment of patients with persistent or recurrent ovarian cancer. , 2013, Gynecologic oncology.

[2]  S. Archer,et al.  Role of Dynamin-Related Protein 1 (Drp1)-Mediated Mitochondrial Fission in Oxygen Sensing and Constriction of the Ductus Arteriosus , 2013, Circulation research.

[3]  M. Oren,et al.  Cisplatin hypersensitivity of testicular germ cell tumors is determined by high constitutive Noxa levels mediated by Oct-4. , 2013, Cancer research.

[4]  Simon C Watkins,et al.  Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes ATM-dependent G2/M arrest and aneuploidy through DNA replication stress , 2012, Journal of Cell Science.

[5]  Yuquan Wei,et al.  NOXA-Induced Alterations in the Bax/Smac Axis Enhance Sensitivity of Ovarian Cancer Cells to Cisplatin , 2012, PloS one.

[6]  L. Galluzzi,et al.  Molecular mechanisms of cisplatin resistance , 2012, Oncogene.

[7]  R. Bast,et al.  Minireview: human ovarian cancer: biology, current management, and paths to personalizing therapy. , 2012, Endocrinology.

[8]  J. Richards,et al.  Minireview: animal models and mechanisms of ovarian cancer development. , 2012, Endocrinology.

[9]  R. Youle,et al.  Predominant requirement of Bax for apoptosis in HCT116 cells is determined by Mcl-1’s inhibitory effect on Bak , 2011, Oncogene.

[10]  J. Levine,et al.  Role of Drp1, a Key Mitochondrial Fission Protein, in Neuropathic Pain , 2011, The Journal of Neuroscience.

[11]  P. Reaper,et al.  Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. , 2011, Nature chemical biology.

[12]  Sang Woo Park,et al.  A selective inhibitor of drp1, mdivi-1, increases retinal ganglion cell survival in acute ischemic mouse retina. , 2011, Investigative ophthalmology & visual science.

[13]  F. Spinella,et al.  Acquisition of Chemoresistance and EMT Phenotype Is Linked with Activation of the Endothelin A Receptor Pathway in Ovarian Carcinoma Cells , 2011, Clinical Cancer Research.

[14]  G. Brumatti,et al.  An ERK-dependent pathway to Noxa expression regulates apoptosis by platinum-based chemotherapeutic drugs , 2010, Oncogene.

[15]  B. Van Houten,et al.  Alterations in bioenergetics due to changes in mitochondrial DNA copy number. , 2010, Methods.

[16]  J. Nunnari,et al.  Small molecule inhibitors of mitochondrial division: tools that translate basic biological research into medicine. , 2010, Chemistry & biology.

[17]  T. Chou.  Drug combination studies and their synergy quantification using the Chou-Talalay method. , 2010, Cancer research.

[18]  Z. Dong,et al.  Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. , 2009, The Journal of clinical investigation.

[19]  R. Kofler,et al.  Noxa: at the tip of the balance between life and death , 2008, Oncogene.

[20]  P. Borst,et al.  High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs , 2008, Proceedings of the National Academy of Sciences.

[21]  T. Kuwana,et al.  Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. , 2008, Developmental cell.

[22]  M. Nachtigal,et al.  Primary culture of ovarian surface epithelial cells and ascites-derived ovarian cancer cells from patients , 2006, Nature Protocols.

[23]  R. Burger,et al.  Use of a dummy (pacifier) during sleep and risk of sudden infant death syndrome (SIDS): population based case-control study , 2005, BMJ : British Medical Journal.

[24]  Dong Wang,et al.  Cellular processing of platinum anticancer drugs , 2005, Nature Reviews Drug Discovery.

[25]  I. Herskowitz,et al.  Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Y. Pommier,et al.  Transcription-coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cells. , 2002, Cancer research.

[27]  E. Alnemri,et al.  Abrogation of Mitochondrial Cytochrome c Release and Caspase-3 Activation in Acquired Multidrug Resistance* , 1998, The Journal of Biological Chemistry.

[28]  B. van de Water,et al.  Cisplatin-induced nephrotoxicity in porcine proximal tubular cells: mitochondrial dysfunction by inhibition of complexes I to IV of the respiratory chain. , 1997, The Journal of pharmacology and experimental therapeutics.

[29]  G. Chu,et al.  Cellular responses to cisplatin. The roles of DNA-binding proteins and DNA repair. , 1994, The Journal of biological chemistry.

[30]  C. Runowicz.  Advances in the screening and treatment of ovarian cancer , 1992, CA: a cancer journal for clinicians.

[31]  A. Pa,et al.  Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. , 1990 .

[32]  J. Mcvie,et al.  Direct diffusion of cis-diamminedichloroplatinum(II) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy. , 1989, Cancer research.

[33]  C. Sorenson,et al.  Influence of cis-diamminedichloroplatinum(II) on DNA synthesis and cell cycle progression in excision repair proficient and deficient Chinese hamster ovary cells. , 1988, Cancer research.

[34]  Yun Feng,et al.  PKD2 mediates multi-drug resistance in breast cancer cells through modulation of P-glycoprotein expression. , 2011, Cancer letters.

[35]  Lorenzo Galluzzi,et al.  Mitochondrial membrane permeabilization in cell death. , 2007, Physiological reviews.

[36]  Kaori Sasai,et al.  Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53 , 2004, Nature Genetics.

[37]  S. Howell,et al.  Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. , 1990, Cancer cells.

[38]  A. Eastman.  The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. , 1987, Pharmacology & therapeutics.