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Effects of Epothilone A in Combination with the Antidiabetic Drugs Metformin and Sitagliptin in HepG2 Human Hepatocellular Cancer Cells: Role of Transcriptional Factors NF-κB and p53
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 Title & Authors
Effects of Epothilone A in Combination with the Antidiabetic Drugs Metformin and Sitagliptin in HepG2 Human Hepatocellular Cancer Cells: Role of Transcriptional Factors NF-κB and p53
Rogalska, Aneta; Sliwinska, Agnieszka; Kasznicki, Jacek; Drzewoski, Jozef; Marczak, Agnieszka;
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Type 2 diabetes mellitus patients are at increased risk of many forms of malignancies, especially of the pancreas, colon and hepatocellular cancer. Unfortunately, little is known of the possible interaction between antidiabetic drugs and anticancer agents. The present study investigates the influence of metformin (MET) and sitagliptin (SITA) on the in vitro anticancer activity of the microtubule depolymerization inhibitor agent epothilone A (EpoA). Hepatocellular liver carcinoma cell line (HepG2) viability and apoptosis were determined by the MTT test and by double staining with PO-PRO-1 and 7-aminoactinomycin D, respectively, after treatment with EpoA, metformin or sitagliptin. The levels of nuclear factor NF- and p53 were evaluated in the presence and absence of inhibitors. While EpoA and MET inhibited HepG2 cell proliferation, SITA did not. EpoA and SITA induced higher p53 levels than MET. All tested drugs increased the level of NF-. Only MET enhanced the proapoptotic effect of EpoA. The EpoA+MET combination evoked the highest cytotoxic effect on HepG2 cells and led to apoptosis independent of p53, decreasing the level of NF-. These findings support the link between NF- and p53 in the modulation of apoptotic effects in HepG2 cells treated by EpoA. Our studies indicate that the combination of EpoA and MET applied in subtoxic doses has a stronger cytotoxic effect on liver cancer cells than each of the compounds alone. The therapeutic advantages of the combination of EpoA with MET may be valuable in the treatment of patients with diabetes mellitus type 2 (T2DM) and liver cancer.
Apoptosis;epothilone A;hepatocarcinoma;metformin;sitagliptin;
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Targeting autophagy as a strategy for drug discovery and therapeutic modulation, Future Medicinal Chemistry, 2017, 9, 3, 335  crossref(new windwow)
Alberti C (2013). Taxane- and epothilone-based chemotherapy: from molecule cargo cytoskeletal logistics to management of castration-resistant prostate carcinoma. Eur Rev Med Pharmacological Sci, 17, 1658-64.

Aldea M, Craciun L, Tomuleasa C, et al (2014). Repositioning metformin in cancer: genetics, drug targets, and new ways of delivery. Tumour Biol, 35, 5101-10. crossref(new window)

An F, Zhao WJ, Tang L, et al (2015). Concentration-dependent differential effects of an epothilone analog on cell cycle and p53 signaling. Oncol Rep.

Aoki M, Nata T, Morishita R, et al (2001). Endothelial apoptosis induced by oxidative stress through activation of NF-kappaB: antiapoptotic effect of antioxidant agents on endothelial cells. Hypertension, 38, 48-55. crossref(new window)

Azlin AH, Looi LM, Cheah PL (2014). Tissue microarray immunohistochemical profiles of p53 and pRB in hepatocellular carcinoma and hepatoblastoma. Asian Pac J Cancer Prev, 15, 3959-63. crossref(new window)

Baldwin AS (2012). Regulation of cell death and autophagy by IKK and NF-kappaB: critical mechanisms in immune function and cancer. Immunological Rev, 246, 327-45. crossref(new window)

Ben Sahra I, Laurent K, Giuliano S, et al (2010). Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res, 70, 2465-75. crossref(new window)

Bost F, Sahra IB, Le Marchand-Brustel Y, et al (2012). Metformin and cancer therapy. Curr Opin Oncol, 24, 103-8. crossref(new window)

Cai X, Hu X, Cai B, et al (2013). Metformin suppresses hepatocellular carcinoma cell growth through induction of cell cycle G1/G0 phase arrest and p21CIP and p27KIP expression and downregulation of cyclin D1 in vitro and in vivo. Oncol Rep, 30, 2449-57. crossref(new window)

Carmichael J, DeGraff WG, Gazdar AF, et al (1987). Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res, 47, 936-42.

Chang AY, Wang M (2013). In-vitro growth inhibition of chemotherapy and molecular targeted agents in hepatocellular carcinoma. Anticancer Drugs, 24, 251-9. crossref(new window)

Chaudhary SC, Kurundkar D, Elmets CA, et al (2012). Metformin, an antidiabetic agent reduces growth of cutaneous squamous cell carcinoma by targeting mTOR signaling pathway. Photochem Photobiol, 88, 1149-56. crossref(new window)

Chen HP, Shieh JJ, Chang CC, et al (2013). Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut, 62, 606-15. crossref(new window)

Chen TM, Lin CC, Huang PT, et al (2011). Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation. J Gastroenterol Hepatol, 26, 858-65. crossref(new window)

Chiang GG, Abraham RT (2007). Targeting the mTOR signaling network in cancer. Trends Mol Med, 13, 433-42. crossref(new window)

Davoudi Z, Akbarzadeh A, Rahmatiyamchi M, et al (2014). Molecular target therapy of AKT and NF-${\kappa}B$ signaling pathways and multidrug resistance by specific cell penetrating inhibitor peptides in HL-60 cells. asian pac j cancer prev, 15, 4353-8. crossref(new window)

Dilokthornsakul P, Chaiyakunapruk N, Termrungruanglert W, et al (2013). The effects of metformin on ovarian cancer: a systematic review. International J Gynecological Cancer, 23, 1544-51. crossref(new window)

Ganesan C, Obulareddy SJ, Fischer JH, et al (2014). Phase I Study of Pazopanib and Ixabepilone in Patients With Solid Tumors. am j clinical oncol.

Giannakakou P, Nakano M, Nicolaou KC, et al (2002). Enhanced microtubule-dependent trafficking and p53 nuclear accumulation by suppression of microtubule dynamics. Proc Natl Acad Sci USA, 99, 10855-60. crossref(new window)

Hadad SM, Hardie DG, Appleyard V, Thompson AM (2014). Effects of metformin on breast cancer cell proliferation, the AMPK pathway and the cell cycle. Clin Transl Oncol, 16, 746-52. crossref(new window)

Hammer S, Sommer A, Fichtner I, et al (2010). Comparative profiling of the novel epothilone, sagopilone, in xenografts derived from primary non-small cell lung cancer. Clin Cancer Res, 16, 1452-65. crossref(new window)

Harris K, Smith L (2013). Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis C. Ann Pharmacother, 47, 1348-52. crossref(new window)

Hayden MS, Ghosh S (2012). NF-kappaB, the first quartercentury: remarkable progress and outstanding questions. Genes Development, 26, 203-34. crossref(new window)

Hofer A, Noe N, Tischner C, et al (2014). Defining the action spectrum of potential PGC-1alpha activators on a mitochondrial and cellular level in vivo. Human molecular genetics.

Huang Y, Fan W (2002). IkappaB kinase activation is involved in regulation of paclitaxel-induced apoptosis in human tumor cell lines. Molecular Pharmacol, 61, 105-13. crossref(new window)

Ismail S, Mayah W, Battia HE, et al (2015). Plasma nuclear factor kappa B and serum peroxiredoxin 3 in early diagnosis of hepatocellular carcinoma. Asian Pac J Cancer Prev, 16, 1657-63. crossref(new window)

Kapahi P, Takahashi T, Natoli G, et al (2000). Inhibition of NF-kappa B activation by arsenite through reaction with a critical cysteine in the activation loop of Ikappa B kinase. J Biological Chemistry, 275, 36062-6. crossref(new window)

Kasznicki J, Sliwinska A, Drzewoski J (2014). Metformin in cancer prevention and therapy. Ann Transl Med, 2, 57.

Lee SH, Son SM, Son DJ, et al (2007). Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization independent activation of the nuclear factorkappaB/IkappaB kinase signal pathway. Molecular Cancer Therapeutics, 6, 2786-97. crossref(new window)

Lenski M, Kazakov A, Marx N, et al (2011). Effects of DPP-4 inhibition on cardiac metabolism and function in mice. J Molecular Cellular Cardiology, 51, 906-18. crossref(new window)

Loong HH, Yeo W (2014). Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma. Onco Targets Ther, 7, 575-85.

Madan E, Gogna R, Bhatt M, et al (2011). Regulation of glucose metabolism by p53: emerging new roles for the tumor suppressor. Oncotarget, 2, 948-57. crossref(new window)

Miyoshi H, Kato K, Iwama H, et al (2014). Effect of the antidiabetic drug metformin in hepatocellular carcinoma in vitro and in vivo. Int J Oncol, 45, 322-32. crossref(new window)

Mok TS, Choi E, Yau D, et al (2006). Effects of patupilone (epothilone B; EPO906), a novel chemotherapeutic agent, in hepatocellular carcinoma: an in vitro study. Oncol, 71, 292-6. crossref(new window)

Otte A, Rauprich F, Hillemanns P, et al (2014). In vitro and in vivo therapeutic approach for a small cell carcinoma of the ovary hypercalcaemic type using a SCCOHT-1 cellular model. Orphanet J Rare Dis, 9, 126. crossref(new window)

Patel S, Singh N, Kumar L (2015). Evaluation of Effects of Metformin in Primary Ovarian Cancer Cells. Asian Pacific J Cancer Prev, 16, 6973-9. crossref(new window)

Rengarajan T, Nandakumar N, Rajendran P, et al (2014). D-pinitol promotes apoptosis in MCF-7 cells via induction of p53 and Bax and inhibition of Bcl-2 and NF-kappaB. Asian Pac J Cancer Prev, 15, 1757-62. crossref(new window)

Rogalska A, Gajek A, Marczak A (2014). Epothilone B induces extrinsic pathway of apoptosis in human SKOV-3 ovarian cancer cells. Toxicol In Vitro, 28, 675-83. crossref(new window)

Rogalska A, Marczak A, Gajek A, et al (2013a). Induction of apoptosis in human ovarian cancer cells by new anticancer compounds, epothilone A and B. Toxicol In Vitro, 27, 239-49. crossref(new window)

Rogalska A, Szula E, Gajek A, et al (2013b). Activation of apoptotic pathway in normal, cancer ovarian cells by epothilone B. Environ Toxicol Pharmacol, 36, 600-10. crossref(new window)

Saito T, Chiba T, Yuki K, et al (2013). Metformin, a diabetes drug, eliminates tumor-initiating hepatocellular carcinoma cells. PloS one, 8, 70010. crossref(new window)

Sangle GV, Lauffer LM, Grieco A, et al (2012). Novel biological action of the dipeptidylpeptidase-IV inhibitor, sitagliptin, as a glucagon-like peptide-1 secretagogue. Endocrinol, 153, 564-73. crossref(new window)

Sliwinska A, Rogalska A, Marczak A, et al (2015). Metformin, but not sitagliptin, enhances WP 631-induced apoptotic HepG2 cell death. Toxicol In Vitro, 29, 1116-23. crossref(new window)

Tan HK, Moad AI, Tan ML (2014). The mTOR signalling pathway in cancer and the potential mTOR inhibitory activities of natural phytochemicals. Asian Pac J Cancer Prev, 15, 6463-75. crossref(new window)

Ueda Y, Richmond A (2006). NF-kappaB activation in melanoma. Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society, 19, 112-24. crossref(new window)

Wang CH, Wey KC, Mo LR, et al (2015). Current trends and recent advances in diagnosis, therapy, and prevention of hepatocellular carcinoma. Asian Pac J Cancer Prev, 16, 3595-604. crossref(new window)

Wardle EN (2001). Nuclear factor kappaB for the nephrologist. Nephrol Dial Transplant, 16, 1764-8. crossref(new window)

Winsel S, Sommer A, Eschenbrenner J, et al (2011). Molecular mode of action and role of TP53 in the sensitivity to the novel epothilone sagopilone (ZK-EPO) in A549 non-small cell lung cancer cells. PloS one, 6, 19273. crossref(new window)

Woudenberg-Vrenken TE, Conde de la Rosa L, Buist-Homan M, et al (2013). Metformin protects rat hepatocytes against bile acid-induced apoptosis. PloS one, 8, 71773. crossref(new window)

Yi G, He Z, Zhou X, et al (2013). Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway. Int J Oncol, 43, 1503-10. crossref(new window)

Zhang H, An F, Tang L, et al (2014). Multiple effects of a novel epothilone analog on cellular processes and signaling pathways regulated by Rac1 GTPase in the human breast cancer cells. Korean J Physiol Pharmacol, 18, 109-20. crossref(new window)

Zhang ZJ, Li S (2014). The prognostic value of metformin for cancer patients with concurrent diabetes: a systematic review and meta-analysis. Diabetes Obes Metab, 16, 707-10. crossref(new window)

Zheng L, Yang W, Wu F, et al (2013). Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clinical Cancer Res, 19, 5372-80. crossref(new window)

Zhou Q, Wong CH, Lau CP, et al (2013). Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma. Int J Hepatol, 2013, 103830.

Zhuang Y, Miskimins WK (2008a). Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Molecular Signal, 3, 18. crossref(new window)

Zhuang Y, Miskimins WK (2008b). Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Mol Signal, 3, 18. crossref(new window)

Zuco V, Zunino F (2008). Cyclic pifithrin-alpha sensitizes wild type p53 tumor cells to antimicrotubule agent-induced apoptosis. Neoplasia, 10, 587-96. crossref(new window)