Nicotinamide Overcomes Doxorubicin Resistance of Breast Cancer Cells through Deregulating SIRT1/Akt Pathway

Author(s): Yingze Wei, Yan Guo, Jianyun Zhou, Kui Dai, Qiang Xu, Xiaoxia Jin*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 19 , Issue 5 , 2019

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Graphical Abstract:


Abstract:

Background and Purpose: Breast cancer is one of the leading causes of cancer deaths in female worldwide. Doxorubicin represents the most common chemotherapy for breast cancer, whereas side effects and development of resistance impede its effect on chemotherapy. Nicotinamide (NAM), serves as the sirtuins’ inhibitor, effectively suppressing various types of cancer. However, the effects of NAM on drug resistance of breast cancer are need to be fully investigated.

Methods: Breast cancer doxorubicin-resistant cells MCF-7/ADR and doxorubicin-sensitive cells MCF-7 were applied in this study. Cell proliferation was assessed by CCK8 and colony-forming assays. Cell migration was evaluated by scratch test and transwell assay while cell apoptosis was measured by TUNEL analysis. Expression levels of SIRT1, phosphate Akt (P-Akt, Ser-473) and Akt were measured using western blot analysis. The interrelation between SIRT1 and Akt was investigated by co-immunoprecipitation assay.

Results: Treatment of nicotinamide combined with doxorubicin effectively inhibited cell growth, suppressed cell migration, and promoted cell apoptosis of MCF7/ADR cells. Mechanistically, nicotinamide translocated SIRT1 from the cell nucleus to cytoplasm, dissociated the connection between SIRT1 and Akt, and consequently decreased expressions of SIRT1, and P-Akt, thereby inhibiting the growth of MCF7/ADR cells.

Conclusions: Our results suggested that the value of nicotinamide is a potential therapeutic agent for breast cancer treatment through downregulating SIRT1/Akt pathway, leading to the valid management of breast cancer patients.

Keywords: Breast cancer, nicotinamide, doxorubicin resistance, SIRT1, Akt, P-Akt.

[1]
Chen, W.; Zheng, R.; Zhang, S.; Zeng, H.; Xia, C.; Zuo, T.; Yang, Z.; Zou, X.; He, J. Cancer incidence and mortality in China, 2013. Cancer Lett., 2017, 401, 63-71.
[2]
Akram, M.; Iqbal, M.; Daniyal, M.; Khan, A.U. Awareness and current knowledge of breast cancer. Biol. Res., 2017, 50(1), 33.
[3]
Kolahdooz, F.; Jang, S.L.; Corriveau, A.; Gotay, C.; Johnston, N.; Sharma, S. Knowledge, attitudes, and behaviours towards cancer screening in indigenous populations: A systematic review. Lancet Oncol., 2014, 15(11), 504-516.
[4]
Liu, M.; Yu, X.; Chen, Z.; Yang, T.; Yang, D.; Liu, Q.; Du, K.; Li, B.; Wang, Z.; Li, S.; Deng, Y.; He, N. Aptamer selection and applications for breast cancer diagnostics and therapy. J. Nanobiotechnology, 2017, 15(1), 81.
[5]
Zhang, X.H.; Hao, S.; Gao, B.; Tian, W.G.; Jiang, Y.; Zhang, S. A network meta-analysis for toxicity of eight chemotherapy regimens in the treatment of metastatic advanced breast cancer. Oncotarget, 2016, 7, 84533-84543.
[6]
Ansari, L.; Shiehzadeh, F.; Taherzadeh, Z.; Nikoofal-Sahlabadi, S.; Momtazi-Borojeni, A.A.; Sahebkar, A.; Eslami, S. The most prevalent side effects of pegylated liposomal doxorubicin monotherapy in women with metastatic breast cancer: a systematic review of clinical trials. Cancer Gene Ther., 2017, 24(5), 189-193.
[7]
Shafei, A.; El-Bakly, W.; Sobhy, A.; Wagdy, O.; Reda, A.; Aboelenin, O.; Marzouk, A.E.; Habak, K.; Mostafa, R.; Ali, M.A.; Ellithy, M. A review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer. Biomed. Pharmacother., 2017, 95, 1209-1218.
[8]
Aniogo, E.C.; George, B.P.A.; Abrahamse, H. Phthalocyanine induced phototherapy coupled with Doxorubicin; a promising novel treatment for breast cancer. Expert Rev. Anticancer Ther., 2017, 17(8), 693-702.
[9]
Karthikeyan, K.; Thappa, D.M. Pellagra and skin. Int. J. Dermatol., 2002, 41(8), 476-481.
[10]
Ishaque, A.; Al-Rubeai, M. Role of vitamins in determining apoptosis and extent of suppression by bcl-2 during hybridoma cell culture. Apoptosis, 2002, 7(3), 231-239.
[11]
Jacobson, E.L.; Giacomoni, P.U.; Roberts, M.J.; Wondrak, G.T.; Jacobson, M.K. Optimizing the energy status of skin cells during solar radiation. J. Photochem. Photobiol. B, 2001, 63(1-3), 141-147.
[12]
Benavente, C.A.; Jacobson, E.L. Niacin restriction upregulates NADPH oxidase and reactive oxygen species (ROS) in human keratinocytes. Free Radic. Biol. Med., 2008, 44(4), 527-537.
[13]
Wang, X.Y.; Wang, J.Z.; Gao, L.; Zhang, F.Y.; Wang, Q.; Liu, K.J.; Xiang, B. Inhibition of nicotinamide phosphoribosyltransferase and depletion of nicotinamide adenine dinucleotide contribute to arsenic trioxide suppression of oral squamous cell carcinoma. Toxicol. Appl. Pharmacol., 2017, 331, 54-61.
[14]
Sawicka-Gutaj, N.; Waligórska-Stachura, J.; Andrusiewicz, M.; Biczysko, M.; Sowiński, J.; Skrobisz, J.; Ruchała, M. Nicotinamide phosphorybosiltransferase overexpression in thyroid malignancies and its correlation with tumor stage and with survivin/survivin DEx3 expression. Tumour Biol., 2015, 36(10), 7859-7863.
[15]
Takao, S.; Chien, W.; Madan, V.; Lin, D.C.; Ding, L.W.; Sun, Q.Y.; Mayakonda, A.; Sudo, M.; Xu, L.; Chen, Y.; Jiang, Y.Y.; Gery, S.; Lill, M.; Park, E.; Senapedis, W.; Baloglu, E.; Müschen, M.; Koeffler, H.P. Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia. Leukemia, 2018, 32(3), 616-625.
[16]
Kim, J.Y.; Lee, H.; Woo, J.; Yue, W.; Kim, K.; Choi, S.; Jang, J.J.; Kim, Y.; Park, I.A.; Han, D.; Ryu, H.S. Reconstruction of pathway modification induced by nicotinamide using multi-omic network analyses in triple negative breast cancer. Sci. Rep., 2017, 7(1), 3466.
[17]
Zheng, J.; Glezerman, I.G.; Sadot, E.; McNeil, A.; Zarama, C.; Gönen, M.; Creasy, J.; Pak, L.M.; Balachandran, V.P.; D’Angelica, M.I.; Allen, P.J.; DeMatteo, R.P.; Kingham, T.P.; Jarnagin, W.R.; Jaimes, E.A. Hypophosphatemia after hepatectomy or pancreatectomy: Role of the nicotinamide phosphoribosyltransferase. J. Am. Coll. Surg., 2017, 225(4), 488-497.
[18]
Dong, G.; Chen, W.; Wang, X.; Yang, X.; Xu, T.; Wang, P.; Zhang, W.; Rao, Y.; Miao, C.; Sheng, C. Small molecule inhibitors simultaneously targeting cancer metabolism and epigenetics: Discovery of novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) dual inhibitors. J. Med. Chem., 2017, 60(19), 7965-7983.
[19]
Vaziri, H.; Dessain, S.K.; Ng Eaton, E.; Imai, S.I.; Frye, R.A.; Pandita, T.K.; Guarente, L.; Weinberg, R.A. hSIR2(SIRT1) functions as an NAD-Dependent p53 Deacetylase. Cell, 2001, 107(2), 149-159.
[20]
Bordone, L.; Guarente, L. Calorie restriction, SIRT1 and metabolism: Understanding longevity. Nat. Rev. Mol. Cell Biol., 2005, 6(4), 298-305.
[21]
Jin, X.; Wei, Y.; Xu, F.; Zhao, M.; Dai, K.; Shen, R.; Yang, S.; Zhang, N. SIRT1 promotes formation of breast cancer through modulating Akt activity. J. Cancer, 2018, 9(11), 2012-2023.
[22]
Zhang, J.G.; Zhao, G.; Qin, Q.; Wang, B.; Liu, L.; Liu, Y.; Deng, S.C.; Tian, K.; Wang, C.Y. Nicotinamide prohibits proliferation and enhances chemosensitivity of pancreatic cancer cells through deregulating SIRT1 and Ras/Akt pathways. Pancreatology, 2013, 13(2), 140-146.
[23]
Jung-Hynes, B.; Nihal, M.; Zhong, W.; Ahmad, N. Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? J. Biol. Chem., 2009, 284(6), 3823-3832.
[24]
Audrito, V.; Vaisitti, T.; Rossi, D.; Gottardi, D.; D’Arena, G.; Laurenti, L.; Gaidano, G.; Malavasi, F.; Deaglio, S. Nicotinamide blocks proliferation and induces apoptosis of chronic lymphocytic leukemia cells through activation of the p53/miR-34a/SIRT1 tumor suppressor network. Cancer Res., 2011, 71(13), 4473-4483.
[25]
Deng, C.X. SIRT1, Is it a tumor promoter or tumor suppressor? Int. J. Biol. Sci., 2009, 5(2), 147-152.
[26]
Chen, W.; Bhatia, R. Roles of SIRT1 in leukemogenesis. Curr. Opin. Hematol., 2013, 20(4), 308-313.
[27]
Han, L.; Liang, X.H.; Chen, L.X.; Bao, S.M.; Yan, Z.Q. SIRT1 is highly expressed in brain metastasis tissues of non-small cell lung cancer (NSCLC) and in positive regulation of NSCLC cell migration. Int. J. Clin. Exp. Pathol., 2013, 6(11), 2357-2365.
[28]
Chu, F.; Chou, P.M.; Zheng, X.; Mirkin, B.L.; Rebbaa, A. Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1. Cancer Res., 2005, 65(22), 10183-10187.
[29]
Lee, M.S.; Jeong, M.H.; Lee, H.W.; Han, H.J.; Ko, A.; Hewitt, S.M.; Kim, J.H.; Chun, K.H.; Chung, J.Y.; Lee, C.; Cho, H.
Song, J. PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis. Nat. Commun., 2015, 6, 7769.
[30]
Tanno, M.; Sakamoto, J.; Miura, T.; Shimamoto, K.; Horio, Y. Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J. Biol. Chem., 2007, 282(9), 6823-6832.
[31]
Rosenberg, M.I.; Parkhurst, S.M. Drosophila Sir2 is required for heterochromatic silencing and by euchromatic Hairy/E(Spl) bHLH repressors in segmentation and sex determination. Cell, 2002, 109(4), 447-458.
[32]
Lain, S.; Hollick, J.J.; Campbell, J.; Staples, O.D.; Higgins, M.; Aoubala, M.; McCarthy, A.; Appleyard, V.; Murray, K.E.; Baker, L.; Thompson, A.; Mathers, J.; Holland, S.J.; Stark, M.J.; Pass, G.; Woods, J.; Lane, D.P.; Westwood, N.J. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell, 2008, 13(5), 454-463.
[33]
Pissios, P. Nicotinamide N-Methyltransferase: More than a vitamin B3 clearance enzyme. Trends Endocrinol. Metab., 2017, 28(5), 340-353.


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Article Details

VOLUME: 19
ISSUE: 5
Year: 2019
Page: [687 - 696]
Pages: 10
DOI: 10.2174/1871520619666190114160457

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