Potentials of PKC in Cancer Progression and Anticancer Drug Development

Author(s): Suman J. Deka, Vishal Trivedi*.

Journal Name: Current Drug Discovery Technologies

Volume 16 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

PKC is a family of serine-threonine kinases which play crucial roles in the regulation of important signal transduction pathways in mammalian cell-biology. These enzymes are themselves regulated by various molecules that can serve as ligands to the regulatory domains and translocate PKC to membrane for activity. The role of PKC in the modulation of both proliferative and apoptotic signaling in cancer has become a subject of immense interest after it was discovered that PKC regulates a myriad of enzymes and transcription factors involved in carcinogenic signaling. Therefore, PKC has served as an attractive target for the development of newer generation of anti-cancer drugs. The following review discusses the potential of PKC to be regarded as a target for anti-cancer therapy. We also review all the molecules that have been discovered so far to be regulators/activators/inhibitors of PKC and also how far these molecules can be considered as potential candidates for anti-cancer drug development based on PKC.

Keywords: Agonist, antagonists, cancer, protein kinase C, metastasis, signal transduction.

[1]
GM C Cells as experimental models The cell: A molecular approach. 2nd ed. Sunderland, MA: Sinauer Associates 2000.
[2]
Keesey RE, Powley TL. Body energy homeostasis. Appetite 2008; 51(3): 442-5.
[3]
Hanahan D. Weinberg robert A. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-74.
[4]
Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signaling pathways in cancer. Oncogene 2007; 26(22): 3279-90.
[5]
Sun XG, Rotenberg SA. Overexpression of protein kinase Calpha in MCF-10A human breast cells engenders dramatic alterations in morphology, proliferation, and motility. Cell Growth Differ 1999; 10(5): 343-52.
[6]
Detjen KM, Brembeck FH, Welzel M, et al. Activation of protein kinase calpha inhibits growth of pancreatic cancer cells via p21(cip)-mediated G(1) arrest. J Cell Sci 2000; 113(Pt 17): 3025-35.
[7]
Frey MR, Clark JA, Leontieva O, Uronis JM, Black AR, Black JD. Protein kinase C signaling mediates a program of cell cycle withdrawal in the intestinal epithelium. J Cell Biol 2000; 151(4): 763-78.
[8]
Jiang XH, Tu SP, Cui JT, et al. Antisense targeting protein kinase C alpha and beta1 inhibits gastric carcinogenesis. Cancer Res 2004; 64(16): 5787-94.
[9]
Wu TT, Hsieh YH, Hsieh YS, Liu JY. Reduction of PKC alpha decreases cell proliferation, migration, and invasion of human malignant hepatocellular carcinoma. J Cell Biochem 2008; 103(1): 9-20.
[10]
Yoshida K. PKCdelta signaling: Mechanisms of DNA damage response and apoptosis. Cell Signal 2007; 19(5): 892-901.
[11]
Nakagawa M, Oliva JL, Kothapalli D, Fournier A, Assoian RK, Kazanietz MG. Phorbol ester-induced G1 phase arrest selectively mediated by protein kinase Cdelta-dependent induction of p21. J Biol Chem 2005; 280(40): 33926-34.
[12]
Aziz MH, Manoharan HT, Church DR, et al. Protein kinase Cepsilon interacts with signal transducers and activators of transcription 3 (Stat3), phosphorylates Stat3Ser727, and regulates its constitutive activation in prostate cancer. Cancer Res 2007; 67(18): 8828-38.
[13]
Takai Y, Kishimoto A, Inoue M, Nishizuka Y. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J Biol Chem 1977; 252(21): 7603-9.
[14]
Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 1982; 257(13): 7847-51.
[15]
Mackay HJ, Twelves CJ. Targeting the protein kinase C family: Are we there yet? Nat Rev Cancer 2007; 7(7): 554-62.
[16]
Pearce LR, Komander D, Alessi DR. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 2010; 11(1): 9-22.
[17]
Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 1995; 9(7): 484-96.
[18]
Tan S-L, Parker PJ. Emerging and diverse roles of protein kinase C in immune cell signaling. Biochem J 2003; 376(Pt 3): 545-52.
[19]
Kang J-H. Protein Kinase C (PKC) Isozymes and Cancer. New J Sci 2014; 2014: 36.
[20]
Antal CE, Newton AC. Tuning the signaling output of protein kinase C. Biochem Soc Trans 2014; 42(6): 1477-83.
[21]
Santiago-Walker AE, Fikaris AJ, Kao GD, Brown EJ, Kazanietz MG, Meinkoth JL. Protein kinase C delta stimulates apoptosis by initiating G1 phase cell cycle progression and S phase arrest. J Biol Chem 2005; 280(37): 32107-14.
[22]
Griner EM, Kazanietz MG. Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 2007; 7(4): 281-94.
[23]
Grossoni VC, Falbo KB, Kazanietz MG, de Kier Joffe ED, Urtreger AJ. Protein kinase C delta enhances proliferation and survival of murine mammary cells. Mol Carcinog 2007; 46(5): 381-90.
[24]
Garg R, Benedetti LG, Abera MB, Wang H, Abba M, Kazanietz MG. Protein kinase C and cancer: What we know and what we do not. Oncogene 2014; 33(45): 5225-37.
[25]
Black AR, Black JD. Protein kinase C signaling and cell cycle regulation. Front Immunol 2012; 3: 423.
[26]
Reddig PJ, Dreckschmidt NE, Zou J, Bourguignon SE, Oberley TD, Verma AK. Transgenic mice overexpressing protein kinase Cε in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion. Cancer Res 2000; 60(3): 595-602.
[27]
Wheeler DL, Martin KE, Ness KJ, et al. Protein kinase C ε Is an endogenous photosensitizer that enhances ultraviolet radiation-induced cutaneous damage and development of squamous cell carcinomas1. Cancer Res 2004; 64(21): 7756-65.
[28]
Hurd C, Rozengurt E. Protein kinase D is sufficient to suppress EGF-induced c-Jun Ser 63 phosphorylation. Biochem Biophys Res Commun 2001; 282(2): 404-8.
[29]
Waldron RT, Whitelegge JP, Faull KF, Rozengurt E. Identification of a novel phosphorylation site in c-jun directly targeted in vitro by protein kinase D. Biochem Biophys Res Commun 2007; 356(2): 361-7.
[30]
Aziz MH, Manoharan HT, Verma AK. Protein kinase C epsilon, which sensitizes skin to sun’s UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3. Cancer Res 2007; 67(3): 1385-94.
[31]
Lopez-Bergami P, Huang C, Goydos JS, et al. Rewired ERK-JNK signaling pathways in melanoma. Cancer Cell 2007; 11(5): 447-60.
[32]
Lopez-Bergami P, Habelhah H, Bhoumik A, Zhang W, Wang LH, Ronai Z. RACK1 mediates activation of JNK by protein kinase C.[corrected]. Molecular Cell 2005; 19(3): 309-20.
[33]
Cruz-Correa M, Shoskes DA, Sanchez P, et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol 2006; 4(8): 1035-8.
[34]
Lee JW, Park JA, Kim SH, et al. Protein kinase C-delta regulates the stability of hypoxia-inducible factor-1 alpha under hypoxia. Cancer Sci 2007; 98(9): 1476-81.
[35]
Gliki G, Wheeler-Jones C, Zachary I. Vascular endothelial growth factor induces protein kinase C (PKC)-dependent Akt/PKB activation and phosphatidylinositol 3′-kinase-mediates PKC delta phosphorylation: role of PKC in angiogenesis. Cell Biol Int 2002; 26(9): 751-9.
[36]
Yoshiji H, Kuriyama S, Ways DK, et al. Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis. Cancer Res 1999; 59(17): 4413-8.
[37]
Liu ZC, Chen XH, Song HX, et al. Snail regulated by PKC/GSK-3beta pathway is crucial for EGF-induced epithelial-mesenchymal transition (EMT) of cancer cells. Cell Tissue Res 2014; 358(2): 491-502.
[38]
Zafar A, Hardy K, Wu F, Li J, Rao S. The role of protein kinase-C theta in control of epithelial to mesenchymal transition and cancer stem cell formation. Genom Data 2015; 3: 28-32.
[39]
Soto-Guzman A, Navarro-Tito N, Castro-Sanchez L, Martinez-Orozco R, Salazar EP. Oleic acid promotes MMP-9 secretion and invasion in breast cancer cells. Clin Exp Metastasis 2010; 27(7): 505-15.
[40]
Lin CW, Hou WC, Shen SC, et al. Quercetin inhibition of tumor invasion via suppressing PKC delta/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis 2008; 29(9): 1807-15.
[41]
Sun R, Gao P, Chen L, et al. Protein kinase C zeta is required for epidermal growth factor-induced chemotaxis of human breast cancer cells. Cancer Res 2005; 65(4): 1433-41.
[42]
Wang J, Wan W, Sun R, et al. Reduction of Akt2 expression inhibits chemotaxis signal transduction in human breast cancer cells. Cell Signal 2008; 20(6): 1025-34.
[43]
Gopalakrishna R, Chen ZH, Gundimeda U. Tobacco smoke tumor promoters, catechol and hydroquinone, induce oxidative regulation of protein kinase C and influence invasion and metastasis of lung carcinoma cells. Proc Natl Acad Sci USA 1994; 91(25): 12233-7.
[44]
Lin KT, Wang YW, Chen CT, Ho CM, Su WH, Jou YS. HDAC inhibitors augmented cell migration and metastasis through induction of PKCs leading to identification of low toxicity modalities for combination cancer therapy. Clin Cancer Res 2012; 18(17): 4691-701.
[45]
Jiang Y, Berk M, Singh LS, et al. KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha. Clin Exp Metastasis 2005; 22(5): 369-76.
[46]
Caponigro F, French RC, Kaye SB. Protein kinase C: A worthwhile target for anticancer drugs? Anticancer Drugs 1997; 8(1): 26-33.
[47]
Yoshida M, Yokokura H, Hidaka H, Ikekawa T, Saijo N. Mechanism of antitumor action of PKC activator, gnidimacrin. Int J Cancer 1998; 77(2): 243-50.
[48]
Schaufelberger DE, Koleck MP, Beutler JA, et al. The large-scale isolation of bryostatin 1 from Bugula neritina following current good manufacturing practices. J Nat Prod 1991; 54(5): 1265-70.
[49]
Hennings H, Blumberg PM, Pettit GR, Herald CL, Shores R, Yuspa SH. Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin. Carcinogenesis 1987; 8(9): 1343-6.
[50]
Ajani JA, Jiang Y, Faust J, et al. A multi-center phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Invest New Drugs 2006; 24(4): 353-7.
[51]
Barr PM, Lazarus HM, Cooper BW, et al. Phase II study of bryostatin 1 and vincristine for aggressive non-Hodgkin lymphoma relapsing after an autologous stem cell transplant. Am J Hematol 2009; 84(8): 484-7.
[52]
Kedei N, Lundberg DJ, Toth A, Welburn P, Garfield SH, Blumberg PM. Characterization of the interaction of ingenol 3-angelate with protein kinase C. Cancer Res 2004; 64(9): 3243-55.
[53]
Hampson P, Chahal H, Khanim F, et al. PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC. Blood 2005; 106(4): 1362-8.
[54]
Ogbourne SM, Suhrbier A, Jones B, et al. Antitumor activity of 3-ingenyl angelate: Plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res 2004; 64(8): 2833-9.
[55]
Le TT, Gardner J, Hoang-Le D, et al. Immunostimulatory cancer chemotherapy using local ingenol-3-angelate and synergy with immunotherapies. Vaccine 2009; 27(23): 3053-62.
[56]
Siller G, Gebauer K, Welburn P, Katsamas J, Ogbourne SM. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study. Australas J Dermatol 2009; 50(1): 16-22.
[57]
Park IC, Park MJ, Rhee CH, et al. Protein kinase C activation by PMA rapidly induces apoptosis through caspase-3/CPP32 and serine protease(s) in a gastric cancer cell line. Int J Oncol 2001; 18(5): 1077-83.
[58]
Itsumi M, Shiota M, Yokomizo A, et al. PMA induces androgen receptor downregulation and cellular apoptosis in prostate cancer cells. J Mol Endocrinol 2014; 53(1): 31-41.
[59]
Han ZT, Tong YK, He LM, et al. 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced increase in depressed white blood cell counts in patients treated with cytotoxic cancer chemotherapeutic drugs. Proc Natl Acad Sci USA 1998; 95(9): 5362-5.
[60]
Shen X, Xiong GL, Jing Y, et al. The protein kinase C agonist prostratin induces differentiation of human myeloid leukemia cells and enhances cellular differentiation by chemotherapeutic agents. Cancer Lett 2015; 356(2 Pt B): 686-96.
[61]
Wang MT, Holderfield M, Galeas J, et al. K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling. Cell 2015; 163(5): 1237-51.
[62]
Szallasi Z, Blumberg PM. Prostratin, a nonpromoting phorbol ester, inhibits induction by phorbol 12-myristate 13-acetate of ornithine decarboxylase, edema, and hyperplasia in CD-1 mouse skin. Cancer Res 1991; 51(19): 5355-60.
[63]
Beans EJ, Fournogerakis D, Gauntlett C, et al. Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo. Proc Natl Acad Sci USA 2013; 110(29): 11698-703.
[64]
Fujiki H, Mori M, Nakayasu M, Terada M, Sugimura T, Moore RE. Indole alkaloids: Dihydroteleocidin B, teleocidin, and lyngbyatoxin A as members of a new class of tumor promoters. Proc Natl Acad Sci USA 1981; 78(6): 3872-6.
[65]
Arcoleo JP, Weinstein IB. Activation of protein kinase C by tumor promoting phorbol esters, teleocidin and aplysiatoxin in the absence of added calcium. Carcinogenesis 1985; 6(2): 213-7.
[66]
Gaveriaux C, Fehr T, Montecino-Rodriguez E, Sanglier JJ, Loor F. Protein kinase C activators of the teleocidin family decrease the IgE-binding capacity of rat basophilic leukemia cells. Int Arch Allergy Appl Immunol 1988; 86(4): 465-71.
[67]
Stahn S, Thelen L, Albrecht I-M, Bitzer J, Henkel T, Teusch NE. Teleocidin A2 inhibits human proteinase-activated receptor 2 signaling in tumor cellsPharmacol Res Perspect 2016; 4(4): e00230- n/a
[68]
Jaken S, Shupnik MA, Blumberg PM, Tashjian AH Jr. Relationship between mezerein-mediated biological responses and phorbol ester receptor occupancy. Cancer Res 1983; 43(1): 11-4.
[69]
Nishio H, Ikegami Y, Segawa T, Nakata Y. Stimulation of calcium sequestration by mezerein, a protein kinase C activator, in saponized rabbit platelets. Gen Pharmacol 1994; 25(3): 413-6.
[70]
Majhi A, Rahman GM, Panchal S, Das J. Binding of curcumin and its long chain derivatives to the activator binding domain of novel protein kinase C. Bioorg Med Chem 2010; 18(4): 1591-8.
[71]
Mahmmoud YA. Modulation of protein kinase C by curcumin; inhibition and activation switched by calcium ions. Br J Pharmacol 2007; 150(2): 200-8.
[72]
Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB, Kondo Y. Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: Role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol 2007; 72(1): 29-39.
[73]
Bachmeier B, Nerlich AG, Iancu CM, et al. The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice. Cell Physiol Biochem 2007; 19(1-4): 137-52.
[74]
Li L, Ahmed B, Mehta K, Kurzrock R. Liposomal curcumin with and without oxaliplatin: Effects on cell growth, apoptosis, and angiogenesis in colorectal cancer. Mol Cancer Ther 2007; 6(4): 1276-82.
[75]
Choudhuri T, Pal S, Das T, Sa G. Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner. J Biol Chem 2005; 280(20): 20059-68.
[76]
Jaiswal AS, Marlow BP, Gupta N, Narayan S. Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 2002; 21(55): 8414-27.
[77]
Bharti AC, Donato N, Singh S, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 2003; 101(3): 1053-62.
[78]
Collett GP, Campbell FC. Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells. Carcinogenesis 2004; 25(11): 2183-9.
[79]
Gray MO, Karliner JS, Mochly-Rosen D. A selective epsilon-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death. J Biol Chem 1997; 272(49): 30945-51.
[80]
Hu H, Mendoza JS, Lowden CT, Ballas LM, Janzen WP. Synthesis and protein kinase C inhibitory activities of balanol analogues with modification of 4-hydroxybenzamido moiety. Bioorg Med Chem 1997; 5(9): 1873-82.
[81]
Defauw JM, Murphy MM, Jagdmann GE, et al. Synthesis and Protein Kinase C Inhibitory Activities of Acyclic Balanol Analogs That Are Highly Selective for Protein Kinase C over Protein Kinase A. J Med Chem 1996; 39(26): 5215-27.
[82]
Kobayashi E, Ando K, Nakano H, et al. Calphostins (UCN-1028), novel and specific inhibitors of protein kinase C. I. Fermentation, isolation, physico-chemical properties and biological activities. J Antibiot (Tokyo) 1989; 42(10): 1470-4.
[83]
Rotenberg SA, Huang MH, Zhu J, Su L, Riedel H. Deletion analysis of protein kinase C inactivation by calphostin C. Mol Carcinog 1995; 12(1): 42-9.
[84]
Takahashi I, Kobayashi E, Asano K, Yoshida M, Nakano H. UCN-01, a selective inhibitor of protein kinase C from Streptomyces. J Antibiot (Tokyo) 1987; 40(12): 1782-4.
[85]
Hanauske AR, Oberschmidt O, Hanauske-Abel H, Lahn MM, Eismann U. Antitumor activity of enzastaurin (LY317615.HCl) against human cancer cell lines and freshly explanted tumors investigated in in-vitro [corrected] soft-agar cloning experiments. Invest New Drugs 2007; 25(3): 205-10.
[86]
Ghobrial IM, Munshi NC, Harris BN, et al. A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma. Am J Hematol 2011; 86(7): 573-8.
[87]
Nwankwo N, Zhang Z, Wang T, et al. Phase I study of enzastaurin and bevacizumab in patients with advanced cancer: safety, efficacy and pharmacokinetics. Invest New Drugs 2013; 31(3): 653-60.
[88]
Crump M, Leppä S, Fayad L, et al. Randomized, Double-Blind, Phase III Trial of Enzastaurin Versus Placebo in Patients Achieving Remission After First-Line Therapy for High-Risk Diffuse Large B-Cell Lymphoma. J Clin Oncol 2016; 34(21): 2484-92.
[89]
Tenzer A, Zingg D, Rocha S, et al. The phosphatidylinositide 3′-kinase/Akt survival pathway is a target for the anticancer and radiosensitizing agent PKC412, an inhibitor of protein kinase C. Cancer Res 2001; 61(22): 8203-10.
[90]
Monnerat C, Henriksson R, Le Chevalier T, et al. Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer. Ann Oncol 2004; 15(2): 316-23.
[91]
Eder JP Jr, Garcia-Carbonero R, Clark JW, et al. A phase I trial of daily oral 4′- N -benzoyl-staurosporine in combination with protracted continuous infusion 5-fluorouracil in patients with advanced solid malignancies. Invest New Drugs 2004; 22(2): 139-50.
[92]
Mizuno K, Saido TC, Ohno S, Tamaoki T, Suzuki K. Staurosporine-related compounds, K252a and UCN-01, inhibit both cPKC and nPKC. FEBS Lett 1993; 330(2): 114-6.
[93]
Monks A, Harris ED, Vaigro-Wolff A, Hose CD, Connelly JW, Sausville EA. UCN-01 enhances the in vitro toxicity of clinical agents in human tumor cell lines. Invest New Drugs 2000; 18(2): 95-107.
[94]
Hotte SJ, Oza A, Winquist EW, et al. Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium study. Ann Oncol 2006; 17(2): 334-40.
[95]
Li T, Christensen SD, Frankel PH, et al. A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma: A California Cancer Consortium trial. Invest New Drugs 2012; 30(2): 741-8.
[96]
Jirousek MR, Gillig JR, Gonzalez CM, et al. (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-d ione (LY333531) and related analogues: Isozyme selective inhibitors of protein kinase C beta. J Med Chem 1996; 39(14): 2664-71.
[97]
Deissler HL, Lang GE. The Protein Kinase C Inhibitor: Ruboxistaurin. Dev Ophthalmol 2016; 55: 295-301.
[98]
Ruboxistaurin: LY 333531. Drugs in R&D 2007; 8(3): 193-9.
[99]
Siomboing X, Gressier B, Dine T, et al. Investigation of the inhibitory effects of chelerythrine chloride on the translocation of the protein kinase C betaI, betaII, zeta in human neutrophils. Farmaco 2001; 56(11): 859-65.
[100]
Chmura SJ, Dolan ME, Cha A, Mauceri HJ, Kufe DW, Weichselbaum RR. In vitro and in vivo activity of protein kinase C inhibitor chelerythrine chloride induces tumor cell toxicity and growth delay in vivo. Clin Cancer Res 2000; 6(2): 737-42.
[101]
Stallings-Mann M, Jamieson L, Regala RP, Weems C, Murray NR, Fields AP. A novel small-molecule inhibitor of protein kinase Ciota blocks transformed growth of non-small-cell lung cancer cells. Cancer Res 2006; 66(3): 1767-74.
[102]
Regala RP, Weems C, Jamieson L, Copland JA, Thompson EA, Fields AP. Atypical protein kinase Ciota plays a critical role in human lung cancer cell growth and tumorigenicity. J Biol Chem 2005; 280(35): 31109-15.
[103]
Mansfield AS, Fields AP, Jatoi A, et al. Phase I dose escalation study of the PKCι inhibitor aurothiomalate for advanced non-small cell lung cancer, ovarian cancer and pancreatic cancer. Anticancer Drugs 2013; 24(10): 1079-83.
[104]
Chu F, O’Brian CA. PKC sulfhydryl targeting by disulfiram produces divergent isozymic regulatory responses that accord with the cancer preventive activity of the thiuram disulfide. Antioxid Redox Signal 2005; 7(7-8): 855-62.
[105]
Fruehauf JP, Trapp V. Reactive oxygen species: an Achilles’ heel of melanoma? Expert Rev Anticancer Ther 2008; 8(11): 1751-7.
[106]
Nechushtan H, Hamamreh Y, Nidal S, et al. A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. The Oncologist 2015; 20(4): 366-7.
[107]
O’Brian CA, Liskamp RM, Solomon DH, Weinstein IB. Inhibition of protein kinase C by tamoxifen. Cancer Res 1985; 45(6): 2462-5.
[108]
Horgan K, Cooke E, Hallett MB, Mansel RE. Inhibition of protein kinase C mediated signal transduction by tamoxifen. Importance for antitumour activity. Biochem Pharmacol 1986; 35(24): 4463-5.
[109]
Young LH, Balin BJ, Weis MT. Go 6983: A fast acting protein kinase C inhibitor that attenuates myocardial ischemia/reperfusion injury. Cardiovasc Drug Rev 2005; 23(3): 255-72.
[110]
Kim HR, Lee KH, Park SJ, et al. Anti-cancer activity and mechanistic features of a NK cell activating molecule. Cancer Immunol Immunother 2009; 58(10): 1691-700.
[111]
Huigsloot M, Tijdens RB, van de Water B. Inhibition of protein kinase Calpha enhances anticancer agent-induced loss of anchorage-independent growth regardless of protection against apoptosis by Bcl-2. Mol Pharmacol 2003; 64(4): 965-73.
[112]
Pajak B, Turowska A, Orzechowski A, Gajkowska B. Bisindolylmaleimide IX facilitates extrinsic and initiates intrinsic apoptosis in TNF-alpha-resistant human colon adenocarcinoma COLO 205 cells. Apoptosis 2008; 13(4): 509-22.
[113]
Caino MC, Lopez-Haber C, Kim J, Mochly-Rosen D, Kazanietz MG. Proteins kinase Cvarepsilon is required for non-small cell lung carcinoma growth and regulates the expression of apoptotic genes. Oncogene 2012; 31(20): 2593-600.
[114]
Kim J, Thorne SH, Sun L, Huang B, Mochly-Rosen D. Sustained inhibition of PKCalpha reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model. Oncogene 2011; 30(3): 323-33.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 2
Year: 2019
Page: [135 - 147]
Pages: 13
DOI: 10.2174/1570163815666180219113614
Price: $65

Article Metrics

PDF: 55
HTML: 3