Plumbagin inhibits tumorigenesis and angiogenesis of ovarian cancer cells in vivo

Angiogenesis is a hallmark of tumor development and metastatic progression, and anti‐angiogenic drugs targeting the VEGF pathway have shown to decrease the disease progression in cancer patients. In this study, we have analyzed the anti‐proliferative and anti‐angiogenic property of plumbagin in cisplatin sensitive, BRCA2 deficient, PEO‐1 and cisplatin resistant, BRCA2 proficient PEO‐4 ovarian cancer cells. Both PEO‐1 and PEO‐4 ovarian cancer cells are sensitive to plumbagin irrespective of BRCA2 status in both normoxia and hypoxia. Importantly, plumbagin treatment effectively inhibits VEGF‐A and Glut‐1 in PEO‐1 and PEO‐4 ovarian cancer cells. We have also analyzed the p53 mutant, cisplatin resistant, and BRCA2 proficient OVCAR‐5 cells. Plumbagin challenge also restricts the VEGF induced pro‐angiogenic signaling in HUVECs and subsequently endothelial cell proliferation. In addition, we observe a significant effect on tumor regression among OVCAR‐5 tumor‐bearing mice treated with plumbagin, which is associated with significant inhibition of Ki67 and vWF expressions. Plumbagin also significantly reduces CD31 expression in an ear angiogenesis assay. Collectively, our studies indicate that plumbagin, as an anti‐cancer agent disrupts growth of ovarian cancer cells through the inhibition of proliferation as well as angiogenesis.

[1]  Aamir Ahmad,et al.  Perspectives on medicinal properties of plumbagin and its analogs , 2012, Medicinal research reviews.

[2]  Mingyao Liu,et al.  Plumbagin inhibits tumour angiogenesis and tumour growth through the Ras signalling pathway following activation of the VEGF receptor‐2 , 2012, British journal of pharmacology.

[3]  M. Mattson,et al.  Plumbagin promotes the generation of astrocytes from rat spinal cord neural progenitors via activation of the transcription factor Stat3 , 2010, Journal of neurochemistry.

[4]  Shi-chuan Chang,et al.  Plumbagin activates ERK1/2 and Akt via superoxide, Src and PI3-kinase in 3T3-L1 cells. , 2010, European journal of pharmacology.

[5]  Jinchao Zhang,et al.  Status of bi- and multi-nuclear platinum anticancer drug development. , 2010, Anti-cancer agents in medicinal chemistry.

[6]  D. Lu,et al.  Plumbagin induces ROS-mediated apoptosis in human promyelocytic leukemia cells in vivo. , 2010, Leukemia research.

[7]  M. Mattson,et al.  Plumbagin, a novel Nrf2/ARE activator, protects against cerebral ischemia , 2010, Journal of neurochemistry.

[8]  D. Mukhopadhyay,et al.  Von Hippel-Lindau Gene Product Modulates TIS11B Expression in Renal Cell Carcinoma , 2009, The Journal of Biological Chemistry.

[9]  F. Couch,et al.  Edinburgh Research Explorer Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma , 2022 .

[10]  S. Agrawal,et al.  Inhibition of Lysine Acetyltransferase KAT3B/p300 Activity by a Naturally Occurring Hydroxynaphthoquinone, Plumbagin* , 2009, The Journal of Biological Chemistry.

[11]  S. Kalloger,et al.  Regulation of HSulf-1 expression by variant hepatic nuclear factor 1 in ovarian cancer. , 2009, Cancer research.

[12]  C. Prives,et al.  Blinded by the Light: The Growing Complexity of p53 , 2009, Cell.

[13]  M. Aziz,et al.  Plumbagin, a medicinal plant-derived naphthoquinone, is a novel inhibitor of the growth and invasion of hormone-refractory prostate cancer. , 2008, Cancer research.

[14]  C. Croce,et al.  MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis , 2008, Proceedings of the National Academy of Sciences.

[15]  David J. Arenillas,et al.  Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer , 2008, Journal of Cell Science.

[16]  M. A. Akbarsha,et al.  Anticancer mechanism of plumbagin, a natural compound, on non-small cell lung cancer cells. , 2008, Anticancer research.

[17]  F. Couch,et al.  Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers , 2008, Nature.

[18]  Shivendra V. Singh,et al.  Plumbagin-induced Apoptosis in Human Prostate Cancer Cells is Associated with Modulation of Cellular Redox Status and Generation of Reactive Oxygen Species , 2008, Pharmaceutical Research.

[19]  P. Kuo,et al.  Plumbagin induces cell cycle arrest and apoptosis through reactive oxygen species/c-Jun N-terminal kinase pathways in human melanoma A375.S2 cells. , 2008, Cancer letters.

[20]  M. R. Pillai,et al.  Radiosensitizing effects of plumbagin in cervical cancer cells is through modulation of apoptotic pathway , 2008, Molecular carcinogenesis.

[21]  G. Srinivas,et al.  Estrogen-dependent cell signaling and apoptosis in BRCA1-blocked BG1 ovarian cancer cells in response to plumbagin and other chemotherapeutic agents. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[22]  A. Berns.  Cancer biology: Can less be more for p53? , 2006, Nature.

[23]  A. Kinghorn,et al.  Silvestrol regulates G2/M checkpoint genes independent of p53 activity. , 2006, Anticancer research.

[24]  B. Aggarwal,et al.  Plumbagin (5-Hydroxy-2-methyl-1,4-naphthoquinone) Suppresses NF-κB Activation and NF-κB-regulated Gene Products Through Modulation of p65 and IκBα Kinase Activation, Leading to Potentiation of Apoptosis Induced by Cytokine and Chemotherapeutic Agents* , 2006, Journal of Biological Chemistry.

[25]  A. Merlo,et al.  Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation* , 2004, Journal of Biological Chemistry.

[26]  A. Dinakar,et al.  Plumbagin induces reactive oxygen species, which mediate apoptosis in human cervical cancer cells , 2004, Molecular carcinogenesis.

[27]  J. Davies,et al.  Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470 , 2004, Nature Medicine.

[28]  G. Srinivas,et al.  Antisense blocking of BRCA1 enhances sensitivity to plumbagin but not tamoxifen in BG‐1 ovarian cancer cells , 2004, Molecular carcinogenesis.

[29]  G. Semenza.  Angiogenesis in ischemic and neoplastic disorders. , 2003, Annual review of medicine.

[30]  S. Powell,et al.  Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation , 2003, Oncogene.

[31]  Aoife M Shannon,et al.  Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. , 2003, Cancer treatment reviews.

[32]  P. Jeggo,et al.  A subset of ATM‐ and ATR‐dependent phosphorylation events requires the BRCA1 protein , 2003, The EMBO journal.

[33]  B. Wiedenmann,et al.  Oxidative Stress Regulates Vascular Endothelial Growth Factor-A Gene Transcription through Sp1- and Sp3-dependent Activation of Two Proximal GC-rich Promoter Elements* , 2003, The Journal of Biological Chemistry.

[34]  C. Conover,et al.  Functional insulin receptors on human epithelial ovarian carcinoma cells: implications for IGF-II mitogenic signaling. , 2002, Endocrinology.

[35]  Toshiyuki Obata,et al.  Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53* , 2002, The Journal of Biological Chemistry.

[36]  Moshe Oren,et al.  Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis , 2002, Oncogene.

[37]  D. Mukhopadhyay,et al.  Tyrosine Residues 951 and 1059 of Vascular Endothelial Growth Factor Receptor-2 (KDR) Are Essential for Vascular Permeability Factor/Vascular Endothelial Growth Factor-induced Endothelium Migration and Proliferation, Respectively* , 2001, The Journal of Biological Chemistry.

[38]  F. Ismail-Beigi,et al.  Regulation of glut1 mRNA by Hypoxia-inducible Factor-1 , 2001, The Journal of Biological Chemistry.

[39]  Johannes Gerdes,et al.  The Ki‐67 protein: From the known and the unknown , 2000, Journal of cellular physiology.

[40]  K. Alitalo,et al.  Signaling via vascular endothelial growth factor receptors. , 1999, Experimental cell research.

[41]  F. Ismail-Beigi,et al.  Dual Control of glut1 Glucose Transporter Gene Expression by Hypoxia and by Inhibition of Oxidative Phosphorylation* , 1997, The Journal of Biological Chemistry.

[42]  A. Puisieux,et al.  Alteration of p53 damage response by tamoxifen treatment. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[43]  M. Fiscella,et al.  A p53-independent Pathway for Activation of WAF1/CIP1 Expression Following Oxidative Stress * , 1995, The Journal of Biological Chemistry.

[44]  A. Godwin,et al.  High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Smyth,et al.  Characterization and properties of nine human ovarian adenocarcinoma cell lines. , 1988, Cancer research.

[46]  H. Yoshida,et al.  Anti-cancer effect of spinach glycoglycerolipids as angiogenesis inhibitors based on the selective inhibition of DNA polymerase activity. , 2011, Mini reviews in medicinal chemistry.

[47]  N. Nakajima,et al.  Acylated catechin derivatives: inhibitors of DNA polymerase and angiogenesis. , 2011, Frontiers in bioscience.

[48]  O. J. Trask,et al.  Development and implementation of three mitogen-activated protein kinase (MAPK) signaling pathway imaging assays to provide MAPK module selectivity profiling for kinase inhibitors: MK2-EGFP translocation, c-Jun, and ERK activation. , 2006, Methods in enzymology.

[49]  B. Aggarwal,et al.  Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) suppresses NF-kappaB activation and NF-kappaB-regulated gene products through modulation of p65 and IkappaBalpha kinase activation, leading to potentiation of apoptosis induced by cytokine and chemotherapeutic agents. , 2006, The Journal of biological chemistry.

[50]  Dian Feng,et al.  Heterogeneity of the Angiogenic Response Induced in Different Normal Adult Tissues by Vascular Permeability Factor/Vascular Endothelial Growth Factor , 2000, Laboratory Investigation.

[51]  M. McKay,et al.  Cancer of the ovary. , 1994, The New England journal of medicine.