Generic placeholder image

Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Mini-Review Article

Idronoxil as an Anticancer Agent: Activity and Mechanisms

Author(s): Kate Porter*, Walter Douglas Fairlie, Olivier Laczka, Frederic Delebecque and John Wilkinson

Volume 20, Issue 5, 2020

Page: [341 - 354] Pages: 14

DOI: 10.2174/1568009620666200102122830

Price: $65


Idronoxil has been the subject of more than 50 peer-reviewed publications over the last two decades. This isoflavone is an intriguing regulator of multiple signal transduction pathways, capable of causing a range of biological effects, including cell cycle arrest, apoptosis, an ability to stimulate the immune system, and inhibition of angiogenesis. These multifaceted actions suggest that idronoxil has the potential to synergize with, or complement, a wide range of cancer therapies. Whilst clinically tested in the past, idronoxil’s journey was discontinued as a result of its low bioavailability in humans when administered either intravenously or orally, though strategies to overcome this issue are currently being explored. Here, we summarize the current literature regarding the key cellular targets of idronoxil and the mechanisms by which idronoxil exerts its anticancer effects, laying a new foundation toward giving this unique molecule a second chance of contributing to the future of cancer treatment.

Keywords: Idronoxil, phenoxodiol, immunomodulation, oncology, apoptosis, cancer therapy, signal transduction modulators.

Graphical Abstract
Shu, X.O.; Zheng, Y.; Cai, H.; Gu, K.; Chen, Z.; Zheng, W.; Lu, W. Soy food intake and breast cancer survival. JAMA, 2009, 302(22), 2437-2443.
[] [PMID: 19996398]
Trock, B.J.; Hilakivi-Clarke, L.; Clarke, R. Meta-analysis of soy intake and breast cancer risk. J. Natl. Cancer Inst., 2006, 98(7), 459-471.
[] [PMID: 16595782]
Yan, L.; Spitznagel, E.L. Meta-analysis of soy food and risk of prostate cancer in men. Int. J. Cancer, 2005, 117(4), 667-669.
[] [PMID: 15945102]
Banerjee, S.; Zhang, Y.; Ali, S.; Bhuiyan, M.; Wang, Z.; Chiao, P.J.; Philip, P.A.; Abbruzzese, J.; Sarkar, F.H. Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res., 2005, 65(19), 9064-9072.
[] [PMID: 16204081]
Moiseeva, E.P.; Almeida, G.M.; Jones, G.D.; Manson, M.M. Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells. Mol. Cancer Ther., 2007, 6(11), 3071-3079.
[] [PMID: 18025290]
Yeh, T.C.; Chiang, P.C.; Li, T.K.; Hsu, J.L.; Lin, C.J.; Wang, S.W.; Peng, C.Y.; Guh, J.H. Genistein induces apoptosis in human hepatocellular carcinomas via interaction of endoplasmic reticulum stress and mitochondrial insult. Biochem. Pharmacol., 2007, 73(6), 782-792.
[] [PMID: 17188247]
Hillman, G.G.; Wang, Y.; Che, M.; Raffoul, J.J.; Yudelev, M.; Kucuk, O.; Sarkar, F.H. Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model. BMC Cancer, 2007, 7, 4.
[] [PMID: 17212824]
Wang, Y.; Raffoul, J.J.; Che, M.; Doerge, D.R.; Joiner, M.C.; Kucuk, O.; Sarkar, F.H.; Hillman, G.G. Prostate cancer treatment is enhanced by genistein in vitro and in vivo in a syngeneic orthotopic tumor model. Radiat. Res., 2006, 166(1 Pt 1), 73-80.
[] [PMID: 16808622]
Yashar, C.M.; Spanos, W.J.; Taylor, D.D.; Gercel-Taylor, C. Potentiation of the radiation effect with genistein in cervical cancer cells. Gynecol. Oncol., 2005, 99(1), 199-205.
[] [PMID: 16083949]
Li, Y.; Ahmed, F.; Ali, S.; Philip, P.A.; Kucuk, O.; Sarkar, F.H. Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells. Cancer Res., 2005, 65(15), 6934-6942.
[] [PMID: 16061678]
Mai, Z.; Blackburn, G.L.; Zhou, J.R. Genistein sensitizes inhibitory effect of tamoxifen on the growth of estrogen receptor-positive and HER2-overexpressing human breast cancer cells. Mol. Carcinog., 2007, 46(7), 534-542.
[] [PMID: 17295235]
Spagnuolo, C.; Russo, G.L.; Orhan, I.E.; Habtemariam, S.; Daglia, M.; Sureda, A.; Nabavi, S.F.; Devi, K.P.; Loizzo, M.R.; Tundis, R.; Nabavi, S.M. Genistein and cancer: Current status, challenges, and future directions. Adv. Nutr., 2015, 6(4), 408-419.
[] [PMID: 26178025]
Joannou, G.E.; Kelly, G.E.; Reeder, A.Y.; Waring, M.; Nelson, C. A urinary profile study of dietary phytoestrogens. The identification and mode of metabolism of new isoflavonoids. J. Steroid Biochem. Mol. Biol., 1995, 54(3-4), 167-184.
[] [PMID: 7662591]
Kelly, G.E.; Husband, A.J. Flavonoid compounds in the prevention and treatment of prostate cancer. Methods Mol. Med., 2003, 81, 377-394.
[] [PMID: 12725132]
Kamsteeg, M.; Rutherford, T.; Sapi, E.; Hanczaruk, B.; Shahabi, S.; Flick, M.; Brown, D.; Mor, G. Phenoxodiol--an isoflavone analog--induces apoptosis in chemoresistant ovarian cancer cells. Oncogene, 2003, 22(17), 2611-2620.
[] [PMID: 12730675]
Aguero, M.F.; Venero, M.; Brown, D.M.; Smulson, M.E.; Espinoza, L.A. Phenoxodiol inhibits growth of metastatic prostate cancer cells. Prostate, 2010, 70(11), 1211-1221.
[] [PMID: 20564423]
Alvero, A.B.; Brown, D.; Montagna, M.; Matthews, M.; Mor, G. Phenoxodiol-Topotecan co-administration exhibit significant anti-tumor activity without major adverse side effects. Cancer Biol. Ther., 2007, 6(4), 612-617.
[] [PMID: 17457041]
Constantinou, A.I.; Mehta, R.; Husband, A. Phenoxodiol, a novel isoflavone derivative, inhibits dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis in female Sprague-Dawley rats. Eur. J. Cancer, 2003, 39(7), 1012-1018.
[] [PMID: 12706372]
Georgaki, S.; Skopeliti, M.; Tsiatas, M.; Nicolaou, K.A.; Ioannou, K.; Husband, A.; Bamias, A.; Dimopoulos, M.A.; Constantinou, A.I.; Tsitsilonis, O.E. Phenoxodiol, an anticancer isoflavene, induces immunomodulatory effects in vitro and in vivo. J. Cell. Mol. Med., 2009, 13(9B), 3929-3938.
[] [PMID: 19220577]
Li, Y.; Huang, X.; Huang, Z.; Feng, J. Phenoxodiol enhances the antitumor activity of gemcitabine in gallbladder cancer through suppressing Akt/mTOR pathway. Cell Biochem. Biophys., 2014, 70(2), 1337-1342.
[] [PMID: 24902539]
McPherson, R.A.; Galettis, P.T.; de Souza, P.L. Enhancement of the activity of phenoxodiol by cisplatin in prostate cancer cells. Br. J. Cancer, 2009, 100(4), 649-655.
[] [PMID: 19209173]
Yao, C.; Wu, S.; Li, D.; Ding, H.; Wang, Z.; Yang, Y.; Yan, S.; Gu, Z. Co-administration phenoxodiol with doxorubicin synergistically inhibit the activity of sphingosine kinase-1 (SphK1), a potential oncogene of osteosarcoma, to suppress osteosarcoma cell growth both in vivo and in vitro. Mol. Oncol., 2012, 6(4), 392-404.
[] [PMID: 22583777]
Alvero, A.B.; O’Malley, D.; Brown, D.; Kelly, G.; Garg, M.; Chen, W.; Rutherford, T.; Mor, G. Molecular mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells. Cancer, 2006, 106(3), 599-608.
[] [PMID: 16388521]
Kluger, H.M.; McCarthy, M.M.; Alvero, A.B.; Sznol, M.; Ariyan, S.; Camp, R.L.; Rimm, D.L.; Mor, G. The X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma, and XIAP cleavage by Phenoxodiol is associated with Carboplatin sensitization. J. Transl. Med., 2007, 5, 6.
[] [PMID: 17257402]
Miyamoto, M.; Takano, M.; Aoyama, T.; Soyama, H.; Ishibashi, H.; Kato, K.; Iwahashi, H.; Takasaki, K.; Kuwahara, M.; Matuura, H.; Sakamoto, T.; Yoshikawa, T.; Furuya, K. Phenoxodiol increases cisplatin sensitivity in ovarian clear cancer cells through XIAP down-regulation and autophagy inhibition. Anticancer Res., 2018, 38(1), 301-306.
[PMID: 29277787]
Sapi, E.; Alvero, A.B.; Chen, W.; O’Malley, D.; Hao, X.Y.; Dwipoyono, B.; Garg, M.; Kamsteeg, M.; Rutherford, T.; Mor, G. Resistance of ovarian carcinoma cells to docetaxel is XIAP dependent and reversible by phenoxodiol. Oncol. Res., 2004, 14(11-12), 567-578.
[] [PMID: 15666998]
De Luca, T.; Morré, D.M.; Morré, D.J. Reciprocal relationship between cytosolic NADH and ENOX2 inhibition triggers sphingolipid-induced apoptosis in HeLa cells. J. Cell. Biochem., 2010, 110(6), 1504-1511.
[] [PMID: 20518072]
Brown, D.M.; Kelly, G.E.; Husband, A.J. Flavonoid compounds in maintenance of prostate health and prevention and treatment of cancer. Mol. Biotechnol., 2005, 30(3), 253-270.
[] [PMID: 15988050]
Morré, D.J.; Chueh, P.J.; Yagiz, K.; Balicki, A.; Kim, C.; Morré, D.M. ECTO-NOX target for the anticancer isoflavene phenoxodiol. Oncol. Res., 2007, 16(7), 299-312.
[] [PMID: 17518268]
Aguero, M.F.; Facchinetti, M.M.; Sheleg, Z.; Senderowicz, A.M. Phenoxodiol, a novel isoflavone, induces G1 arrest by specific loss in cyclin-dependent kinase 2 activity by p53-independent induction of p21WAF1/CIP1. Cancer Res., 2005, 65(8), 3364-3373.
[] [PMID: 15833870]
Herst, P.M.; Petersen, T.; Jerram, P.; Baty, J.; Berridge, M.V. The antiproliferative effects of phenoxodiol are associated with inhibition of plasma membrane electron transport in tumour cell lines and primary immune cells. Biochem. Pharmacol., 2007, 74(11), 1587-1595.
[] [PMID: 17904534]
Isono, M.; Sato, A.; Asano, T.; Okubo, K.; Asano, T. Evaluation of therapeutic potential of phenoxodiol; a novel isoflavone analog; in renal cancer cells. Anticancer Res., 2018, 38(10), 5709-5716.
[] [PMID: 30275191]
Gamble, J.R.; Xia, P.; Hahn, C.N.; Drew, J.J.; Drogemuller, C.J.; Brown, D.; Vadas, M.A. Phenoxodiol, an experimental anticancer drug, shows potent antiangiogenic properties in addition to its antitumour effects. Int. J. Cancer, 2006, 118(10), 2412-2420.
[] [PMID: 16353157]
Herst, P.M.; Davis, J.E.; Neeson, P.; Berridge, M.V.; Ritchie, D.S. The anti-cancer drug, phenoxodiol, kills primary myeloid and lymphoid leukemic blasts and rapidly proliferating T cells. Haematologica, 2009, 94(7), 928-934.
[] [PMID: 19535345]
Brown, D.M.; Heaton, A.; Husband, A.J. Idronoxil. Drugs Future, 2008, 33, 844-860.
de Souza, P.L.; Liauw, W.; Links, M.; Pirabhahar, S.; Kelly, G.; Howes, L.G. Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol), a novel isoflav-3-ene, in patients with advanced cancer. Cancer Chemother. Pharmacol., 2006, 58(4), 427-433.
[] [PMID: 16463060]
Choueiri, T.K.; Mekhail, T.; Hutson, T.E.; Ganapathi, R.; Kelly, G.E.; Bukowski, R.M. Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer. Ann. Oncol., 2006, 17(5), 860-865.
[] [PMID: 16524966]
Howes, J.B.; de Souza, P.L.; West, L.; Huang, L.J.; Howes, L.G. Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer. BMC Clin. Pharmacol., 2011, 11, 1.
[] [PMID: 21291562]
Kelly, M.G.; Mor, G.; Husband, A.; O’Malley, D.M.; Baker, L.; Azodi, M.; Schwartz, P.E.; Rutherford, T.J. Phase II evaluation of phenoxodiol in combination with cisplatin or paclitaxel in women with platinum/taxane-refractory/resistant epithelial ovarian, fallopian tube, or primary peritoneal cancers. Int. J. Gynecol. Cancer, 2011, 21(4), 633-639.
[] [PMID: 21412168]
Alvero, A.B.; Kelly, M.; Rossi, P.; Leiser, A.; Brown, D.; Rutherford, T.; Mor, G. Anti-tumor activity of phenoxodiol: from bench to clinic. Future Oncol., 2008, 4(4), 475-482.
[] [PMID: 18684059]
Choueiri, T.K.; Wesolowski, R.; Mekhail, T.M. Phenoxodiol: isoflavone analog with antineoplastic activity. Curr. Oncol. Rep., 2006, 8(2), 104-107.
[] [PMID: 16507219]
Mor, G.; Fu, H.H.; Alvero, A.B. Phenoxodiol, a novel approach for the treatment of ovarian cancer. Curr. Opin. Investig. Drugs, 2006, 7(6), 542-548.
[PMID: 16784025]
Saif, M.W.; Tytler, E.; Lansigan, F.; Brown, D.M.; Husband, A.J. Flavonoids, phenoxodiol, and a novel agent, triphendiol, for the treatment of pancreaticobiliary cancers. Expert Opin. Investig. Drugs, 2009, 18(4), 469-479.
[] [PMID: 19278301]
Silasi, D.A.; Alvero, A.B.; Rutherford, T.J.; Brown, D.; Mor, G. Phenoxodiol: pharmacology and clinical experience in cancer monotherapy and in combination with chemotherapeutic drugs. Expert Opin. Pharmacother., 2009, 10(6), 1059-1067.
[] [PMID: 19364253]
de Souza, P. Preclinical and phase I studies of phenoxodiol: A translational approach for the development of a novel isoflavone for the treatment of prostate cancer; University of New South Wales: Sydney, 2009.
Fotopoulou, C.; Vergote, I.; Mainwaring, P.; Bidzinski, M.; Vermorken, J.B.; Ghamande, S.A.; Harnett, P.; Del Prete, S.A.; Green, J.A.; Spaczynski, M.; Blagden, S.; Gore, M.; Ledermann, J.; Kaye, S.; Gabra, H. Weekly AUC2 carboplatin in acquired platinum-resistant ovarian cancer with or without oral phenoxodiol, a sensitizer of platinum cytotoxicity: the phase III OVATURE multicenter randomized study. Ann. Oncol., 2014, 25(1), 160-165.
[] [PMID: 24318743]
Vocks, I.; Capp, A. rial in Progress: NOX66 in combination with Palliative Radiotherapy in patients with CRPC – a Phase 1 safety and dose finding study Poster at COSA Annual Meeting, Perth, 2018.
Baviskar, P.; Bedse, A.; Sadique, S.; Kunde, V.; Jaiswal, S. Drug delivery on rectal absorption: Suppositories. Int. J. Pharm. Sci. Rev. Res., 2013, 21, 70-76.
Constantinou, A.I.; Husband, A. Phenoxodiol [2H-1-benzopyran-7-0;1;2-[4-hydroxyphenyl]]; a novel isoflavone derivative; inhibits DNA topoisomerase II by stabilizing the cleavable complex. Anticancer Res., 2002, 22, 2581-2585.
[PMID: 12529967]
Mahoney, S.; Arfuso, F.; Rogers, P.; Hisheh, S.; Brown, D.; Millward, M.; Dharmarajan, A. Cytotoxic effects of the novel isoflavone, phenoxodiol, on prostate cancer cell lines. J. Biosci., 2012, 37(1), 73-84.
[] [PMID: 22357205]
Mahoney, S.; Arfuso, F.; Millward, M.; Dharmarajan, A. The effects of phenoxodiol on the cell cycle of prostate cancer cell lines. Cancer Cell Int., 2014, 14(1), 110.
[] [PMID: 25400509]
Klein, R.; Brown, D.; Turnley, A.M. Phenoxodiol protects against Cisplatin induced neurite toxicity in a PC-12 cell model. BMC Neurosci., 2007, 8, 61.
[] [PMID: 17672914]
Fink, M.; Bhuyan, A.A.M.; Nürnberg, B.; Faggio, C.; Lang, F. Triggering of eryptosis, the suicidal erythrocyte death, by phenoxodiol. Naunyn Schmiedebergs Arch. Pharmacol., 2019, 392(10), 1311-1318.
[] [PMID: 31280326]
Tilley, A.J.; Zanatta, S.D.; Qin, C.X.; Kim, I.K.; Seok, Y.M.; Stewart, A.; Woodman, O.L.; Williams, S.J. 2-Morpholinoisoflav-3-enes as flexible intermediates in the synthesis of phenoxodiol, isophenoxodiol, equol and analogues: vasorelaxant properties, estrogen receptor binding and Rho/RhoA kinase pathway inhibition. Bioorg. Med. Chem., 2012, 20(7), 2353-2361.
[] [PMID: 22377671]
Wu, L.Y.; De Luca, T.; Watanabe, T.; Morré, D.M.; Morré, D.J. Metabolite modulation of HeLa cell response to ENOX2 inhibitors EGCG and phenoxodiol. Biochim. Biophys. Acta, 2011, 1810(8), 784-789.
[] [PMID: 21571040]
Yu, F.; Watts, R.N.; Zhang, X.D.; Borrow, J.M.; Hersey, P. Involvement of BH3-only proapoptotic proteins in mitochondrial-dependent Phenoxodiol-induced apoptosis of human melanoma cells. Anticancer Drugs, 2006, 17(10), 1151-1161.
[] [PMID: 17075314]
el-Deiry, W.S.; Tokino, T.; Velculescu, V.E.; Levy, D.B.; Parsons, R.; Trent, J.M.; Lin, D.; Mercer, W.E.; Kinzler, K.W.; Vogelstein, B. WAF1, a potential mediator of p53 tumor suppression. Cell, 1993, 75(4), 817-825.
[] [PMID: 8242752]
Harper, J.W.; Adami, G.R.; Wei, N.; Keyomarsi, K.; Elledge, S.J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell, 1993, 75(4), 805-816.
[] [PMID: 8242751]
Macleod, K.F.; Sherry, N.; Hannon, G.; Beach, D.; Tokino, T.; Kinzler, K.; Vogelstein, B.; Jacks, T. p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes Dev., 1995, 9(8), 935-944.
[] [PMID: 7774811]
González, T.; Seoane, M.; Caamaño, P.; Viñuela, J.; Domínguez, F.; Zalvide, J. Inhibition of Cdk4 activity enhances translation of p27kip1 in quiescent Rb-negative cells. J. Biol. Chem., 2003, 278(15), 12688-12695.
[] [PMID: 12566456]
Serrano, M.; Hannon, G.J.; Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature, 1993, 366(6456), 704-707.
[] [PMID: 8259215]
Yeh, Y.Y.; Chen, R.; Hessler, J.; Mahoney, E.; Lehman, A.M.; Heerema, N.A.; Grever, M.R.; Plunkett, W.; Byrd, J.C.; Johnson, A.J. Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia. Oncotarget, 2015, 6(5), 2667-2679.
[] [PMID: 25596730]
Lanasa, M.C.; Andritsos, L.; Brown, J.R.; Gabrilove, J.; Caligaris-Cappio, F.; Ghia, P.; Larson, R.A.; Kipps, T.J.; Leblond, V.; Milligan, D.W.; Janssens, A.; Johnson, A.J.; Heerema, N.A.; Bühler, A.; Stilgenbauer, S.; Devin, J.; Hallek, M.; Byrd, J.C.; Grever, M.R. Final results of EFC6663: A multicenter, international, phase 2 study of alvocidib for patients with fludarabine-refractory chronic lymphocytic leukemia. Leuk. Res., 2015, 39(5), 495-500.
[] [PMID: 25804339]
Aubrey, B.J.; Kelly, G.L.; Janic, A.; Herold, M.J.; Strasser, A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ., 2018, 25, 104-113.
Merino, D.; Kelly, G.L.; Lessene, G.; Wei, A.H.; Roberts, A.W.; Strasser, A. BH3-mimetic drugs: Blazing the trail for new cancer medicines. Cancer Cell, 2018, 34(6), 879-891.
[] [PMID: 30537511]
Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol., 2007, 35(4), 495-516.
[] [PMID: 17562483]
Adams, J.M.; Cory, S. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ., 2018, 25, 27-36.
Danial, N.N.; Korsmeyer, S.J. Cell death: critical control points. Cell, 2004, 116(2), 205-219.
[] [PMID: 14744432]
Ashkenazi, A. Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions. J. Clin. Invest., 2015, 125(2), 487-489.
[] [PMID: 25642709]
Wiezorek, J.; Holland, P.; Graves, J. Death receptor agonists as a targeted therapy for cancer. Clin. Cancer Res., 2010, 16(6), 1701-1708.
[] [PMID: 20197482]
Safa, A.R. Roles of c-FLIP in apoptosis; necroptosis and autophagy. J. Carcinog. Mutagen., 2013, 6, 003.
Tsuchiya, Y.; Nakabayashi, O.; Nakano, H. FLIP the switch: Regulation of apoptosis and necroptosis by cFLIP. Int. J. Mol. Sci., 2015, 16(12), 30321-30341.
[] [PMID: 26694384]
Kataoka, T.; Schröter, M.; Hahne, M.; Schneider, P.; Irmler, M.; Thome, M.; Froelich, C.J.; Tschopp, J. FLIP prevents apoptosis induced by death receptors but not by perforin/granzyme B, chemotherapeutic drugs, and gamma irradiation. J. Immunol., 1998, 161(8), 3936-3942.
[PMID: 9780161]
Scaffidi, C.; Schmitz, I.; Krammer, P.H.; Peter, M.E. The role of c-FLIP in modulation of CD95-induced apoptosis. J. Biol. Chem., 1999, 274(3), 1541-1548.
[] [PMID: 9880531]
Powell, J.A.; Lewis, A.C.; Zhu, W.; Toubia, J.; Pitman, M.R.; Wallington-Beddoe, C.T.; Moretti, P.A.; Iarossi, D.; Samaraweera, S.E.; Cummings, N.; Ramshaw, H.S.; Thomas, D.; Wei, A.H.; Lopez, A.F.; D’Andrea, R.J.; Lewis, I.D.; Pitson, S.M. Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia. Blood, 2017, 129(6), 771-782.
[] [PMID: 27956387]
Akbar Boojar, M.M.; Akbar Boojar, M.M.; Golmohammad, S. Ceramide pathway: A novel approach to cancer chemotherapy. Egyptian J. Basic Appl. Sci., 2018, 5, 237-244.
Ponnusamy, S.; Selvam, S.P.; Mehrotra, S.; Kawamori, T.; Snider, A.J.; Obeid, L.M.; Shao, Y.; Sabbadini, R.; Ogretmen, B. Communication between host organism and cancer cells is transduced by systemic sphingosine kinase 1/sphingosine 1-phosphate signalling to regulate tumour metastasis. EMBO Mol. Med., 2012, 4(8), 761-775.
[] [PMID: 22707406]
Ogretmen, B.; Hannun, Y.A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer, 2004, 4(8), 604-616.
[] [PMID: 15286740]
Rego, A.; Trindade, D.; Chaves, S.R.; Manon, S.; Costa, V.; Sousa, M.J.; Côrte-Real, M. The yeast model system as a tool towards the understanding of apoptosis regulation by sphingolipids. FEMS Yeast Res., 2014, 14(1), 160-178.
[] [PMID: 24103214]
Boojar, M.M.A.; Boojar, M.M.A.; Golmohammad, S.; Bahrehbar, I. Data on cell survival, apoptosis, ceramide metabolism and oxidative stress in A-494 renal cell carcinoma cell line treated with hesperetin and hesperetin-7-O-acetate. Data Brief, 2018, 20, 596-601.
[] [PMID: 30197917]
Gouazé-Andersson, V.; Flowers, M.; Karimi, R.; Fabriás, G.; Delgado, A.; Casas, J.; Cabot, M.C. Inhibition of acid ceramidase by a 2-substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N-(4-hydroxyphenyl) retinamide. Prostate, 2011, 71(10), 1064-1073.
[] [PMID: 21557271]
Morad, S.A.F.; Levin, J.C.; Tan, S-F.; Fox, T.E.; Feith, D.J.; Cabot, M.C. Novel off-target effect of tamoxifen--inhibition of acid ceramidase activity in cancer cells. Biochim. Biophys. Acta, 2013, 1831(12), 1657-1664.
[] [PMID: 23939396]
Yagiz, K.; Wu, L.Y.; Kuntz, C.P.; James Morré, D.; Morré, D.M. Mouse embryonic fibroblast cells from transgenic mice overexpressing tNOX exhibit an altered growth and drug response phenotype. J. Cell. Biochem., 2007, 101(2), 295-306.
[] [PMID: 17115410]
De Luca, T.; Bosneaga, E.; Morré, D.M.; Morré, D.J. Downstream targets of altered sphingolipid metabolism in response to inhibition of ENOX2 by phenoxodiol. Biofactors, 2008, 34(3), 253-260.
[] [PMID: 19734127]
De Luca, T.; Morré, D.M.; Zhao, H.; Morré, D.J. NAD+/NADH and/or CoQ/CoQH2 ratios from plasma membrane electron transport may determine ceramide and sphingosine-1-phosphate levels accompanying G1 arrest and apoptosis. Biofactors, 2005, 25(1-4), 43-60.
[] [PMID: 16873929]
Lipson, E.J.; Drake, C.G. Ipilimumab: An anti-CTLA-4 antibody for metastatic melanoma. Clin. Cancer Res., 2011, 17(22), 6958-6962.
[] [PMID: 21900389]
Brahmer, J.R.; Hammers, H.; Lipson, E.J. Nivolumab: Targeting PD-1 to bolster antitumor immunity. Future Oncol., 2015, 11(9), 1307-1326.
[] [PMID: 25798726]
Khoja, L.; Butler, M.O.; Kang, S.P.; Ebbinghaus, S.; Joshua, A.M. Pembrolizumab. J. Immunother. Cancer, 2015, 3, 36.
[] [PMID: 26288737]
Vivier, E.; Raulet, D.H.; Moretta, A.; Caligiuri, M.A.; Zitvogel, L.; Lanier, L.L.; Yokoyama, W.M.; Ugolini, S. Innate or adaptive immunity? The example of natural killer cells. Science, 2011, 331(6013), 44-49.
[] [PMID: 21212348]
Ames, E.; Canter, R.J.; Grossenbacher, S.K.; Mac, S.; Chen, M.; Smith, R.C.; Hagino, T.; Perez-Cunningham, J.; Sckisel, G.D.; Urayama, S.; Monjazeb, A.M.; Fragoso, R.C.; Sayers, T.J.; Murphy, W.J. NK cells preferentially target tumor cells with a cancer stem cell phenotype. J. Immunol., 2015, 195(8), 4010-4019.
[] [PMID: 26363055]
Pietra, G.; Manzini, C.; Rivara, S.; Vitale, M.; Cantoni, C.; Petretto, A.; Balsamo, M.; Conte, R.; Benelli, R.; Minghelli, S.; Solari, N.; Gualco, M.; Queirolo, P.; Moretta, L.; Mingari, M.C. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res., 2012, 72(6), 1407-1415.
[] [PMID: 22258454]
Sconocchia, G.; Arriga, R.; Tornillo, L.; Terracciano, L.; Ferrone, S.; Spagnoli, G.C. Melanoma cells inhibit NK cell functions. Cancer Res., 2012, 72(20), 5428-5429.
[] [PMID: 23047870]
Parkhurst, M.R.; Riley, J.P.; Dudley, M.E.; Rosenberg, S.A. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin. Cancer Res., 2011, 17(19), 6287-6297.
[] [PMID: 21844012]
Rueff, J.; Medinger, M.; Heim, D.; Passweg, J.; Stern, M. Lymphocyte subset recovery and outcome after autologous hematopoietic stem cell transplantation for plasma cell myeloma. Biol. Blood Marrow Transplant., 2014, 20(6), 896-899.
[] [PMID: 24631739]
Sakamoto, N.; Ishikawa, T.; Kokura, S.; Okayama, T.; Oka, K.; Ideno, M.; Sakai, F.; Kato, A.; Tanabe, M.; Enoki, T.; Mineno, J.; Naito, Y.; Itoh, Y.; Yoshikawa, T. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J. Transl. Med., 2015, 13, 277.
[] [PMID: 26303618]
Guillerey, C.; Huntington, N.D.; Smyth, M.J. Targeting natural killer cells in cancer immunotherapy. Nat. Immunol., 2016, 17(9), 1025-1036.
[] [PMID: 27540992]
Abdalla, A.M.E.; Xiao, L.; Ullah, M.W.; Yu, M.; Ouyang, C.; Yang, G. Current challenges of cancer anti-angiogenic therapy and the promise of nanotherapeutics. Theranostics, 2018, 8(2), 533-548.
[] [PMID: 29290825]
Ramjiawan, R.R.; Griffioen, A.W.; Duda, D.G. Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? Angiogenesis, 2017, 20(2), 185-204.
[] [PMID: 28361267]
Assoun, S.; Brosseau, S.; Steinmetz, C.; Gounant, V.; Zalcman, G. Bevacizumab in advanced lung cancer: state of the art. Future Oncol., 2017, 13(28), 2515-2535.
[] [PMID: 28812378]
Minion, L.E.; Tewari, K.S. The safety and efficacy of bevacizumab in the treatment of patients with recurrent or metastatic cervical cancer. Expert Rev. Anticancer Ther., 2017, 17(3), 191-198.
[] [PMID: 27748633]
Rossi, L.; Verrico, M.; Zaccarelli, E.; Papa, A.; Colonna, M.; Strudel, M.; Vici, P.; Bianco, V.; Tomao, F. Bevacizumab in ovarian cancer: A critical review of phase III studies. Oncotarget, 2017, 8(7), 12389-12405.
[] [PMID: 27852039]
Nomura, T.; Yamasaki, M.; Nomura, Y.; Mimata, H. Expression of the inhibitors of apoptosis proteins in cisplatin-resistant prostate cancer cells. Oncol. Rep., 2005, 14(4), 993-997.
[] [PMID: 16142363]
Sasaki, H.; Sheng, Y.; Kotsuji, F.; Tsang, B.K. Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells. Cancer Res., 2000, 60(20), 5659-5666.
[PMID: 11059757]
Zhang, Y.; Huang, F.; Luo, Q.; Wu, X.; Liu, Z.; Chen, H.; Huang, Y. Inhibition of XIAP increases carboplatin sensitivity in ovarian cancer. OncoTargets Ther., 2018, 11, 8751-8759.
[] [PMID: 30584333]
Schniewind, B.; Christgen, M.; Kurdow, R.; Haye, S.; Kremer, B.; Kalthoff, H.; Ungefroren, H. Resistance of pancreatic cancer to gemcitabine treatment is dependent on mitochondria-mediated apoptosis. Int. J. Cancer, 2004, 109(2), 182-188.
[] [PMID: 14750167]
Wang, J.; Jia, R.; Zhang, Y.; Xu, X.; Song, X.; Zhou, Y.; Zhang, H.; Ge, S.; Fan, X. The role of Bax and Bcl-2 in gemcitabine-mediated cytotoxicity in uveal melanoma cells. Tumour Biol., 2014, 35(2), 1169-1175.
[] [PMID: 24014050]
Datta, A.; Loo, S.Y.; Huang, B.; Wong, L.; Tan, S.S.L.; Tan, T.Z.; Lee, S-C.; Thiery, J.P.; Lim, Y.C.; Yong, W.P.; Lam, Y.; Kumar, A.P.; Yap, C.T. SPHK1 regulates proliferation and survival responses in triple-negative breast cancer. Oncotarget, 2014, 5(15), 5920-5933.
[] [PMID: 25153718]
Shah, M.A.; Schwartz, G.K. Cell cycle-mediated drug resistance: an emerging concept in cancer therapy. Clin. Cancer Res., 2001, 7(8), 2168-2181.
[PMID: 11489790]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy