Berberine Effects on NFκB, HIF1A and NFE2L2/AP-1 Pathways in HeLa Cells

Author(s): Anna Belanova, Darya Beseda, Victor Chmykhalo, Alisa Stepanova, Mariya Belousova, Vera Khrenkova, Nikolaos Gavalas, Peter Zolotukhin*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 19 , Issue 4 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Berberine has multitudinous anti-cancer stem cells effects making it a highly promising candidate substance for the next-generation cancer therapy. However, berberine modes of action predispose it to significant side-effects that probably limit its clinical testing and application.

Materials and Methods: HeLa cells were treated with two concentrations of berberine (30 and 100 µM) for 24 hours to assess the functioning of the NFE2L2/AP-1, NFκB and HIF1A pathways using 22 RNAs expression qPCR-based analysis.

Results: Berberine effects appeared to be highly dose-dependent, with the lower concentration being capable of suppressing the NFκB functioning and the higher concentration causing severe signaling side-effects seen in the HIF1A pathway and the NFE2L2 sub-pathways, and especially and more importantly in the AP-1 sub-pathway.

Conclusion: The results of the study suggest that berberine has clinically valuable anti-NFκB effects however jeopardized by its side effects on the HIF1A and especially NFE2L2/AP-1 pathways, its therapeutic window phenomenon and its cancer type-specificity. These, however, may be ameliorated using the cocktail approach, provided there is enough data on signaling effects of berberine.

Keywords: Berberine, HeLa cells, NFκB, HIF1A, NFE2L2, AP-1, pre-mRNA, mRNA, signaling pathways.

Bruttel, V.S.; Wischhusen, J. Cancer stem cell immunology: Key to understanding tumorigenesis and tumor immune escape? Front. Immunol., 2014, 5, 360.
Sarkar, T.R.; Battula, V.L.; Werden, S.J.; Vijay, G.V.; Ramirez-Peña, E.Q.; Taube, J.H.; Chang, J.T.; Miura, N.; Porter, W.; Sphyris, N.; Andreeff, M.; Mani, S.A. GD3 synthase regulates epithelial-mesenchymal transition and metastasis in breast cancer. Oncogene, 2015, 34(23), 2958-2967.
Zuo, Q.F.; Zhang, R.; Li, B.S.; Zhao, Y.L.; Zhuang, Y.; Yu, T.; Gong, L.; Li, S.; Xiao, B.; Zou, Q.M. MicroRNA-141 inhibits tumor growth and metastasis in gastric cancer by directly targeting transcriptional co-activator with PDZ-binding motif, TAZ. Cell Death Dis., 2015, 6, e1623.
Qi, H.W.; Xin, L.Y.; Xu, X.; Ji, X.X.; Fan, L.H. Epithelial-to-mesenchymal transition markers to predict response of Berberine in suppressing lung cancer invasion and metastasis. J. Transl. Med., 2014, 12, 22.
Tsang, C.M.; Cheung, Y.C.; Lui, V.W.; Yip, Y.L.; Zhang, G.; Lin, V.W.; Cheung, K.C.; Feng, Y.; Tsao, S.W. Berberine suppresses tumorigenicity and growth of nasopharyngeal carcinoma cells by inhibiting STAT3 activation induced by tumor associated fibroblasts. BMC Cancer, 2013, 13, 619.
Zhu, L.Q.; Zhen, Y.F.; Zhang, Y.; Guo, Z.X.; Dai, J.; Wang, X.D. Salinomycin activates AMP-activated protein kinase-dependent autophagy in cultured osteoblastoma cells: A negative regulator against cell apoptosis. PLoS One, 2013, 8(12), e84175.
Ning, X.; Shu, J.; Du, Y.; Ben, Q.; Li, Z. Therapeutic strategies targeting cancer stem cells. Cancer Biol. Ther., 2013, 14(4), 295-303.
Preissner, S.; Dunkel, M.; Hoffmann, M.F.; Preissner, S.C.
Genov, N.; Rong, W.W.; Preissner, R.; Seeger, K. Drug cocktail optimization in chemotherapy of cancer. PLoS One, 2012, 7(12), e51020.
Ma, X.; Zhou, J.; Zhang, C.X.; Li, X.Y.; Li, N.; Ju, R.J.; Shi, J.F.; Sun, M.G.; Zhao, W.Y.; Mu, L.M.; Yan, Y.; Lu, W.L. Modulation of drug-resistant membrane and apoptosis proteins of breast cancer stem cells by targeting berberine liposomes. Biomaterials, 2013, 34(18), 4452-4465.
Tsang, C.M.; Cheung, K.C.; Cheung, Y.C.; Man, K.; Lui, V.W.; Tsao, S.W.; Feng, Y. Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma. Biochim. Biophys. Acta, 2015, 1852(3), 541-551.
Chu, S.C.; Yu, C.C.; Hsu, L.S.; Chen, K.S.; Su, M.Y.; Chen, P.N. Berberine reverses epithelial-to-mesenchymal transition and inhibits metastasis and tumor-induced angiogenesis in human cervical cancer cells. Mol. Pharmacol., 2014, 86(6), 609-623.
Li, W.; Hua, B.; Saud, S.M.; Lin, H.; Hou, W.; Matter, M.S.; Jia, L.; Colburn, N.H.; Young, M.R. Berberine regulates AMP Table activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice. Mol. Carcinog., 2015, 54(10), 1096-1109.
Hamsa, T.P.; Kuttan, G. Antiangiogenic activity of berberine is mediated through the downregulation of hypoxia-inducible factor-1, VEGF, and proinflammatory mediators. Drug Chem. Toxicol., 2012, 35(1), 57-70.
Feng, M.; Luo, X.; Gu, C.; Li, Y.; Zhu, X.; Fei, J. Systematic analysis of berberine-induced signaling pathway between miRNA clusters and mRNAs and identification of mir-99a ∼ 125b cluster function by seed-targeting inhibitors in multiple myeloma cells. RNA Biol., 2015, 12(1), 82-91.
Puthdee, N.; Seubwai, W.; Vaeteewoottacharn, K.; Boonmars, T.; Cha’on, U.; Phoomak, C.; Wongkham, S. Berberine Induces cell cycle arrest in cholangiocarcinoma cell lines via inhibition of NF-κB and STAT3 pathways. Biol. Pharm. Bull., 2017, 40(6), 751-757.
Li, X.; Zhao, S.J.; Shi, H.L.; Qiu, S.P.; Xie, J.Q.; Wu, H.; Zhang, B.B.; Wang, Z.T.; Yuan, J.Y.; Wu, X.J. Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells. Oncol. Rep., 2014, 32(6), 2777-2788.
Goto, H.; Kariya, R.; Shimamoto, M.; Kudo, E.; Taura, M.; Katano, H.; Okada, S. Antitumor effect of berberine against primary effusion lymphoma via inhibition of NF-κB pathway. Cancer Sci., 2012, 103(4), 775-781.
Singh, T.; Vaid, M.; Katiyar, N.; Sharma, S.; Katiyar, S.K. Berberine, an isoquinoline alkaloid, inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E2 and prostaglandin E2 receptors. Carcinogenesis, 2011, 32(1), 86-92.
Kuo, H.P.; Chuang, T.C.; Tsai, S.C.; Tseng, H.H.; Hsu, S.C.; Chen, Y.C.; Kuo, C.L.; Kuo, Y.H.; Liu, J.Y.; Kao, M.C. Berberine, an isoquinoline alkaloid, inhibits the metastatic potential of breast cancer cells via Akt pathway modulation. J. Agric. Food Chem., 2012, 60(38), 9649-9658.
Liu, S.J.; Yin, C.X.; Ding, M.C.; Xia, S.Y.; Shen, Q.M.; Wu, J.D. Berberine suppresses in vitro migration of human aortic smooth muscle cells through the inhibitions of MMP-2/9, u-PA, AP-1, and NF-κB. BMB Rep., 2014, 47(7), 388-392.
Wang, X.; Wang, N.; Li, H.; Liu, M.; Cao, F.; Yu, X.; Zhang, J.; Tan, Y.; Xiang, L.; Feng, Y. Up-regulation of PAI-1 and down-regulation of uPA are involved in suppression of invasiveness and motility of hepatocellular carcinoma cells by a natural compound berberine. Int. J. Mol. Sci., 2016, 17(4), 577.
Hu, H.Y.; Li, K.P.; Wang, X.J.; Liu, Y.; Lu, Z.G.; Dong, R.H.; Guo, H.B.; Zhang, M.X. Set9, NF-κB, and microRNA-21 mediate berberine-induced apoptosis of human multiple myeloma cells. Acta Pharmacol. Sin., 2013, 34(1), 157-166.
Liu, S.J.; Yin, C.X.; Ding, M.C.; Wang, Y.Z.; Wang, H. Berberine inhibits tumor necrosis factor-α-induced expression of inflammatory molecules and activation of nuclear factor-κB via the activation of AMPK in vascular endothelial cells. Mol. Med. Rep., 2015, 12(4), 5580-5586.
Song, S.; Qiu, M.; Chu, Y.; Chen, D.; Wang, X.; Su, A.; Wu, Z. Downregulation of cellular c-Jun N-terminal protein kinase and NF-κB activation by berberine may result in inhibition of herpes simplex virus replication. Antimicrob. Agents Chemother., 2014, 58(9), 5068-5078.
Chao, D.C.; Lin, L.J.; Kao, S.T.; Huang, H.C.; Chang, C.S.; Liang, J.A.; Wu, S.L.; Hsiang, C.Y.; Ho, T.Y. Inhibitory effects of Zuo-Jin-Wan and its alkaloidal ingredients on activator protein 1, nuclear factor-κB, and cellular transformation in HepG2 cells. Fitoterapia, 2011, 82(4), 696-703.
Zhang, J.; Cao, H.; Zhang, B.; Cao, H.; Xu, X.; Ruan, H.; Yi, T.; Tan, L.; Qu, R.; Song, G.; Wang, B.; Hu, T. Berberine potently attenuates intestinal polyps growth in ApcMin mice and familial adenomatous polyposis patients through inhibition of Wnt signalling. J. Cell. Mol. Med., 2013, 17(11), 1484-1493.
Sengupta, D.; Chowdhury, K.D.; Chatterjee, S.; Sarkar, A.; Paul, S.; Sur, P.K.; Sadhukhan, G.C. Modulation of adenylate cyclase signaling in association with MKK3/6 stabilization under combination of SAC and berberine to reduce HepG2 cell survivability. Apoptosis, 2017, 22(11), 1362-1379.
Diab, S.; Fidanzi, C.; Léger, D.Y.; Ghezali, L.; Millot, M.; Martin, F.; Azar, R.; Esseily, F.; Saab, A.; Sol, V.; Diab-Assaf, M.; Liagre, B. Berberis libanotica extract targets NF-κB/COX-2, PI3K/Akt and mitochondrial/caspase signalling to induce human erythroleukemia cell apoptosis. Int. J. Oncol., 2015, 47(1), 220-230.
Hu, W.Q.; Wang, W.; Fang, D.L.; Yin, X.F. Identification of biological targets of therapeutic intervention for hepatocellular carcinoma by integrated bioinformatical analysis. Med. Sci. Monit., 2018, 24, 3450-3461.
Li, M.; Zhang, M.; Zhang, Z.L.; Liu, N.; Han, X.Y.; Liu, Q.C.; Deng, W.J.; Liao, C.X. Induction of apoptosis by berberine in hepatocellular carcinoma HepG2 cells via downregulation of NF-κB. Oncol. Res., 2017, 25(2), 233-239.
Cao, M.; Wang, P.; Sun, C.; He, W.; Wang, F. Amelioration of IFN-γ and TNF-α-induced intestinal epithelial barrier dysfunction by berberine via suppression of MLCK-MLC phosphorylation signaling pathway. PLoS One, 2013, 8(5), e61944.
Lin, S.; Tsai, S.C.; Lee, C.C.; Wang, B.W.; Liou, J.Y.; Shyu, K.G. Berberine inhibits HIF-1alpha expression via enhanced proteolysis. Mol. Pharmacol., 2004, 66(3), 612-619.
Mao, L.; Chen, Q.; Gong, K.; Xu, X.; Xie, Y.; Zhang, W.; Cao, H.; Hu, T.; Hong, X.; Zhan, Y.Y. Berberine decelerates glucose metabolism via suppression of mTOR‑dependent HIF‑1α protein synthesis in colon cancer cells. Oncol. Rep., 2018, 39(5), 2436-2442.
Pan, Y.; Shao, D.; Zhao, Y.; Zhang, F.; Zheng, X.; Tan, Y.; He, K.; Li, J.; Chen, L. Berberine reverses hypoxia-induced chemoresistance in breast cancer through the inhibition of AMPK- HIF-1α. Int. J. Biol. Sci., 2017, 13(6), 794-803.
Zhang, Q.; Zhang, C.; Yang, X.; Yang, B.; Wang, J.; Kang, Y.; Wang, Z.; Li, D.; Huang, G.; Ma, Z.; Sun, X.; Cai, J.; Tao, G.; Dai, S.; Mao, W.; Ma, J. Berberine inhibits the expression of hypoxia induction factor-1alpha and increases the radiosensitivity of prostate cancer. Diagn. Pathol., 2014, 9, 98.
Fu, L.; Chen, W.; Guo, W.; Wang, J.; Tian, Y.; Shi, D.; Zhang, X.; Qiu, H.; Xiao, X.; Kang, T.; Huang, W.; Wang, S.; Deng, W. Berberine Targets AP-2/hTERT, NF-κB/COX-2, HIF-1α/VEGF and cytochrome-c/caspase signaling to suppress human cancer cell growth. PLoS One, 2013, 8(7), e69240.
Yang, X.; Yang, B.; Cai, J.; Zhang, C.; Zhang, Q.; Xu, L.; Qin, Q.; Zhu, H.; Ma, J.; Tao, G.; Cheng, H.; Sun, X. Berberine enhances radiosensitivity of esophageal squamous cancer by targeting HIF-1α in vitro and in vivo. Cancer Biol. Ther., 2013, 14(11), 1068-1073.
Zhang, C.; Yang, X.; Zhang, Q.; Yang, B.; Xu, L.; Qin, Q.; Zhu, H.; Liu, J.; Cai, J.; Tao, G.; Ma, J.; Ge, X.; Zhang, S.; Cheng, H.; Sun, X. Berberine radiosensitizes human nasopharyngeal carcinoma by suppressing hypoxia-inducible factor-1α expression. Acta Otolaryngol., 2014, 134(2), 185-192.
Choi, S.B.; Park, J.B.; Song, T.J.; Choi, S.Y. Molecular mechanism of HIF-1-independent VEGF expression in a hepatocellular carcinoma cell line. Int. J. Mol. Med., 2011, 28(3), 449-454.
Kim, S.H.; Shin, E.J.; Kim, E.D.; Bayaraa, T.; Frost, S.C.; Hyun, C.K. Berberine activates GLUT1-mediated glucose uptake in 3T3-L1 adipocytes. Biol. Pharm. Bull., 2007, 30(11), 2120-2125.
Seo, Y.S.; Yim, M.J.; Kim, B.H.; Kang, K.R.; Lee, S.Y.; Oh, J.S.; You, J.S.; Kim, S.G.; Yu, S.J.; Lee, G.J.; Kim, D.K.; Kim, C.S.; Kim, J.S.; Kim, J.S. Berberine-induced anticancer activities in FaDu head and neck squamous cell carcinoma cells. Oncol. Rep., 2015, 34(6), 3025-3034.
Lund, E.L.; Høg, A.; Olsen, M.W.; Hansen, L.T.; Engelholm, S.A.; Kristjansen, P.E. Differential regulation of VEGF, HIF1alpha and angiopoietin-1, -2 and -4 by hypoxia and ionizing radiation in human glioblastoma. Int. J. Cancer, 2004, 108(6), 833-838.
Wang, L.; Guan, X.; Zhang, J.; Jia, Z.; Wei, D.; Li, Q.; Yao, J.; Xie, K. Targeted inhibition of Sp1-mediated transcription for antiangiogenic therapy of metastatic human gastric cancer in orthotopic nude mouse models. Int. J. Oncol., 2008, 33(1), 161-167.
Wang, J.; Kang, M.; Wen, Q.; Qin, Y.T.; Wei, Z.X.; Xiao, J.J.; Wang, R.S. Berberine sensitizes nasopharyngeal carcinoma cells to radiation through inhibition of Sp1 and EMT. Oncol. Rep., 2017, 37(4), 2425-2432.
Chen, J.; Wu, F.X.; Luo, H.L.; Liu, J.J.; Luo, T.; Bai, T.; Li, L.Q.; Fan, X.H. Berberine upregulates miR-22-3p to suppress hepatocellular carcinoma cell proliferation by targeting Sp1. Am. J. Transl. Res., 2016, 8(11), 4932-4941.
Li, J.; Liu, F.; Jiang, S.; Liu, J.; Chen, X.; Zhang, S.; Zhao, H. Berberine hydrochloride inhibits cell proliferation and promotes apoptosis of non-small cell lung cancer via the suppression of the MMP2 and Bcl-2/Bax signaling pathways. Oncol. Lett., 2018, 15(5), 7409-7414.
Kim, S.; Oh, S.J.; Lee, J.; Han, J.; Jeon, M.; Jung, T.; Lee, S.K.; Bae, S.Y.; Kim, J.; Gil, W.H.; Kim, S.W.; Lee, J.E.; Nam, S.J. Berberine suppresses TPA-induced fibronectin expression through the inhibition of VEGF secretion in breast cancer cells. Cell. Physiol. Biochem., 2013, 32(5), 1541-1550.
Chidambara Murthy, K.N.; Jayaprakasha, G.K.; Patil, B.S. The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells. Eur. J. Pharmacol., 2012, 688(1-3), 14-21.
Jie, S.; Li, H.; Tian, Y.; Guo, D.; Zhu, J.; Gao, S.; Jiang, L. Berberine inhibits angiogenic potential of Hep G2 cell line through VEGF down-regulation in vitro. J. Gastroenterol. Hepatol., 2011, 26(1), 179-185.
Chen, S.; Yin, C.; Lao, T.; Liang, D.; He, D.; Wang, C.; Sang, N. AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol. Cell Cycle, 2015, 14(15), 2520-2536.
Zhang, H. HIF-1 suppresses lipid catabolism to promote cancer progression. Mol. Cell. Oncol., 2015, 2(4), e980184.
Park, H.S.; Kim, J.H.; Sun, B.K.; Song, S.U.; Suh, W.; Sung, J.H. Hypoxia induces glucose uptake and metabolism of adipose‑derived stem cells. Mol. Med. Rep., 2016, 14(5), 4706-4714.
Yu, J.; Li, J.; Zhang, S.; Xu, X.; Zheng, M.; Jiang, G.; Li, F. IGF-1 induces hypoxia-inducible factor 1α-mediated GLUT3 expression through PI3K/Akt/mTOR dependent pathways in PC12 cells. Brain Res., 2012, 1430, 18-24.
Silva, J.L.; Giannocco, G.; Furuya, D.T.; Lima, G.A.; Moraes, P.A.; Nachef, S.; Bordin, S.; Britto, L.R.; Nunes, M.T.; Machado, U.F. NF-kappaB, MEF2A, MEF2D and HIF1-a involvement on insulin- and contraction-induced regulation of GLUT4 gene expression in soleus muscle. Mol. Cell. Endocrinol., 2005, 240(1-2), 82-93.
Park, S.W.; Kim, J.H.; Kim, K.E.; Jeong, M.H.; Park, H.; Park, B.; Suh, Y.G.; Park, W.J.; Kim, J.H. Beta-lapachone inhibits pathological retinal neovascularization in oxygen-induced retinopathy via regulation of HIF-1α. J. Cell. Mol. Med., 2014, 18(5), 875-884.
Moon, D.O.; Choi, Y.H.; Kim, N.D.; Park, Y.M.; Kim, G.Y. Anti-inflammatory effects of beta-lapachone in lipopolysaccharide-stimulated BV2 microglia. Int. Immunopharmacol., 2007, 7(4), 506-514.
Lim, J.Y.; Kim, Y.S.; Kim, K.M.; Min, S.J.; Kim, Y. B-carotene inhibits neuroblastoma tumorigenesis by regulating cell differentiation and cancer cell stemness. Biochem. Biophys. Res. Commun., 2014, 450(4), 1475-1480.
Ciurea, M.E.; Georgescu, A.M.; Purcaru, S.O.; Artene, S.A.; Emami, G.H.; Boldeanu, M.V.; Tache, D.E.; Dricu, A. Cancer stem cells: biological functions and therapeutically targeting. Int. J. Mol. Sci., 2014, 15(5), 8169-8185.
Ning, X.; Shu, J.; Du, Y.; Ben, Q.; Li, Z. Therapeutic strategies targeting cancer stem cells. Cancer Biol. Ther., 2013, 14(4), 295-303.
Mahata, S.; Bharti, A.C.; Shukla, S.; Tyagi, A.; Husain, S.A.; Das, B.C. Berberine modulates AP-1 activity to suppress HPV transcription and downstream signaling to induce growth arrest and apoptosis in cervical cancer cells. Mol. Cancer, 2011, 10, 39.
Cheng, C.C.; Hsueh, C.M.; Liang, K.W.; Ting, C.T.; Wen, C.L.; Hsu, S.L. Role of JNK and c-Jun signaling pathway in regulation of human serum paraoxonase 1 gene transcription by berberine in human HepG2 cells. Eur. J. Pharmacol., 2011, 650(2-3), 519-525.
Jing, W.; Safarpour, Y.; Zhang, T.; Guo, P.; Chen, G.; Wu, X.; Fu, Q.; Wang, Y. Berberine upregulates P-Glycoprotein in human caco-2 cells and in an experimental model of colitis in the rat via activation of Nrf2-dependent mechanisms. J. Pharmacol. Exp. Ther., 2018, 366(2), 332-340.
Sun, Y.; Yuan, X.; Zhang, F.; Han, Y.; Chang, X.; Xu, X.; Li, Y.; Gao, X. Berberine ameliorates fatty acid-induced oxidative stress in human hepatoma cells. Sci. Rep., 2017, 7(1), 11340.
Dinesh, P.; Rasool, M. Berberine, an isoquinoline alkaloid suppresses TXNIP mediated NLRP3 inflammasome activation in MSU crystal stimulated RAW 264.7 macrophages through the upregulation of Nrf2 transcription factor and alleviates MSU crystal induced inflammation in rats. Int. Immunopharmacol., 2017, 44, 26-37.
Zhang, C.; Li, C.; Chen, S.; Li, Z.; Jia, X.; Wang, K.; Bao, J.; Liang, Y.; Wang, X.; Chen, M.; Li, P.; Su, H.; Wan, J.B.; Lee, S.M.Y.; Liu, K.; He, C. Berberine protects against 6-OHDA-induced neurotoxicity in PC12 cells and zebrafish through hormetic mechanisms involving PI3K/AKT/Bcl-2 and Nrf2/HO-1 pathways. Redox Biol., 2017, 11, 1-11.
Mukherjee, A.A.; Kandhare, A.D.; Bodhankar, S.L. Elucidation of protective efficacy of pentahydroxy flavone isolated from Madhuca indica against arsenite-induced cardiomyopathy: Role of Nrf-2, PPAR-γ, c-fos and c-jun. Environ. Toxicol. Pharmacol., 2017, 56, 172-185.
Zeng, Y.; Shen, Z.; Gu, W.; Wu, M. Bioinformatics analysis to identify action targets in NCI-N87 gastric cancer cells exposed to quercetin. Pharm. Biol., 2018, 56(1), 393-398.
Surh, Y.J.; Han, S.S.; Keum, Y.S.; Seo, H.J.; Lee, S.S. Inhibitory effects of curcumin and capsaicin on phorbol ester-induced activation of eukaryotic transcription factors, NF-kappaB and AP-1. Biofactors, 2000, 12(1-4), 107-112.
Teymouri, M.; Barati, N.; Pirro, M.; Sahebkar, A. Biological and pharmacological evaluation of dimethoxycurcumin: A metabolically stable curcumin analogue with a promising therapeutic potential. J. Cell. Physiol., 2018, 233(1), 124-140.
Hu, Y.; Fu, L. Targeting cancer stem cells: A new therapy to cure cancer patients. Am. J. Cancer Res., 2012, 2(3), 340-356.
De Marco, F. Oxidative stress and HPV carcinogenesis. Viruses, 2013, 5(2), 708-731.
Wang, J.; Yi, J. Cancer cell killing via ROS: To increase or decrease, that is the question. Cancer Biol. Ther., 2008, 7(12), 1875-1884.
Ohnuma, T.; Sakamoto, K.; Shinoda, A.; Takagi, C.; Ohno, S.; Nishiyama, T.; Ogura, K.; Hiratsuka, A. Procyanidins from Cinnamomi Cortex promote proteasome-independent degradation of nuclear Nrf2 through phosphorylation of insulin-like growth factor-1 receptor in A549 cells. Arch. Biochem. Biophys., 2017, 635, 66-73.
Sharma, P.K.; Varshney, R. 2-Deoxy-D-glucose and 6-aminonicotinamide-mediated Nrf2 down regulation leads to radiosensitization of malignant cells via abrogation of GSH-mediated defense. Free Radic. Res., 2012, 46(12), 1446-1457.
Ma, X.; Zhang, J.; Liu, S.; Huang, Y.; Chen, B.; Wang, D. Nrf2 knockdown by shRNA inhibits tumor growth and increases efficacy of chemotherapy in cervical cancer. Cancer Chemother. Pharmacol., 2012, 69(2), 485-494.
Chowdhury, A.M.M.A.; Katoh, H.; Hatanaka, A.; Iwanari, H.; Nakamura, N.; Hamakubo, T.; Natsume, T.; Waku, T.; Kobayashi, A. Multiple regulatory mechanisms of the biological function of NRF3 (NFE2L3) control cancer cell proliferation. Sci. Rep., 2017, 7(1), 12494.
Sun, X.; Li, Y.; Li, W.; Zhang, B.; Wang, A.J.; Sun, J.; Mikule, K.; Jiang, Z.; Li, C.J. Selective induction of necrotic cell death in cancer cells by beta-lapachone through activation of DNA damage response pathway. Cell Cycle, 2006, 5(17), 2029-2035.
He, T.; Banach-Latapy, A.; Vernis, L.; Dardalhon, M.; Chanet, R.; Huang, M.E. Peroxiredoxin 1 knockdown potentiates β-lapachone cytotoxicity through modulation of reactive oxygen species and mitogen-activated protein kinase signals. Carcinogenesis, 2013, 34(4), 760-769.
Ma, X.; Huang, X.; Moore, Z.; Huang, G.; Kilgore, J.A.; Wang, Y.; Hammer, S.; Williams, N.S.; Boothman, D.A.; Gao, J. Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy. J. Control. Release, 2015, 200, 201-211.
Park, H.J.; Choi, E.K.; Choi, J.; Ahn, K.J.; Kim, E.J.; Ji, I.M.; Kook, Y.H.; Ahn, S.D.; Williams, B.; Griffin, R.; Boothman, D.A.; Lee, C.K.; Song, C.W. Heat-induced up-regulation of NAD(P)H: Quinone oxidoreductase potentiates anticancer effects of beta-lapachone. Clin. Cancer Res., 2005, 11, 8866-8871.
Muto, Y.; Fujii, J.; Shidoji, Y.; Moriwaki, H.; Kawaguchi, T.; Noda, T. Growth retardation in human cervical dysplasia-derived cell lines by beta-carotene through down-regulation of epidermal growth factor receptor. Am. J. Clin. Nutr., 1995, 62(6)(Suppl.), 1535S-1540S.
Sowmya, P.R.; Arathi, B.P.; Vijay, K.; Baskaran, V.; Lakshminarayana, R. Role of different vehicles in carotenoids delivery and their influence on cell viability, cell cycle progression, and induction of apoptosis in HeLa cells. Mol. Cell. Biochem., 2015, 406(1-2), 245-253.
Kim, Y.S.; Lee, H.A.; Lim, J.Y.; Kim, Y.; Jung, C.H.; Yoo, S.H.; Kim, Y. β-Carotene inhibits neuroblastoma cell invasion and metastasis in vitro and in vivo by decreasing level of hypoxia-inducible factor-1α. J. Nutr. Biochem., 2014, 25(6), 655-664.
Yang, C.M.; Yen, Y.T.; Huang, C.S.; Hu, M.L. Growth inhibitory efficacy of lycopene and β-carotene against androgen-independent prostate tumor cells xenografted in nude mice. Mol. Nutr. Food Res., 2011, 55(4), 606-612.
Deng, X.; Zhao, X.; Lan, Z.; Jiang, J.; Yin, W.; Chen, L. Anti-tumor effects of flavonoids from the ethnic medicine Docynia delavayi (Franch.) Schneid. and its possible mechanism. J. Med. Food, 2014, 17(7), 787-894.
Gismondi, A.; Reina, G.; Orlanducci, S.; Mizzoni, F.; Gay, S.; Terranova, M.L.; Canini, A. Nanodiamonds coupled with plant bioactive metabolites: a nanotech approach for cancer therapy. Biomaterials, 2015, 38, 22-35.
Li, N.; Sun, C.; Zhou, B.; Xing, H.; Ma, D.; Chen, G.; Weng, D. Low concentration of quercetin antagonizes the cytotoxic effects of anti-neoplastic drugs in ovarian cancer. PLoS One, 2014, 9(7), e100314.
Gang, W.; Jie, W.J.; Ping, Z.L. Ming du, S.; Ying, L.J.; Lei, W.; Fang, Y. Liposomal quercetin: evaluating drug delivery in vitro and biodistribution in vivo. Expert Opin. Drug Deliv., 2012, 9(6), 599-613.
Zhang, F.J.; Zhang, H.S.; Liu, Y.; Huang, Y.H. Curcumin inhibits Ec109 cell growth via an AMPK-mediated metabolic switch. Life Sci., 2015, 134, 49-55.
Paulraj, F.; Abas, F.; Lajis, N.H.; Othman, I.; Hassan, S.S.; Naidu, R. The curcumin analogue 1,5-Bis(2-hydroxyphenyl)-1,4-pentadiene-3-one induces apoptosis and downregulates E6 and E7 oncogene expression in HPV16 and HPV18-infected cervical cancer cells. Molecules, 2015, 20(7), 11830-11860.
Yang, X.; Li, Z.; Wang, N.; Li, L.; Song, L.; He, T.; Sun, L.; Wang, Z.; Wu, Q.; Luo, N.; Yi, C.; Gong, C. Curcumin-encapsulated polymeric micelles suppress the development of colon cancer in vitro and in vivo. Sci. Rep., 2015, 5, 10322.
Huang, C.; Ma, W.; Dong, Z. Inhibitory effects of ascorbic acid on AP-1 activity and transformation of JB6 cells. Int. J. Oncol., 1996, 8(2), 389-393.
Pires, A.S.; Marques, C.R.; Encarnação, J.C.; Abrantes, A.M.; Marques, I.A.; Laranjo, M.; Oliveira, R.; Casalta-Lopes, J.E.; Gonçalves, A.C.; Sarmento-Ribeiro, A.B.; Botelho, M.F. Ascorbic acid chemosensitizes colorectal cancer cells and synergistically inhibits tumor growth. Front. Physiol., 2018, 9, 911.
Chen, M.F.; Yang, C.M.; Su, C.M.; Liao, J.W.; Hu, M.L. Inhibitory effect of vitamin C in combination with vitamin K3 on tumor growth and metastasis of Lewis lung carcinoma xenografted in C57BL/6 mice. Nutr. Cancer, 2011, 63(7), 1036-1043.
Lee, J.; Jung, E.; Lee, J.; Huh, S.; Hwang, C.H.; Lee, H.Y.; Kim, E.J.; Cheon, J.M.; Hyun, C.G.; Kim, Y.S.; Park, D. Emodin inhibits TNF alpha-induced MMP-1 expression through suppression of activator protein-1 (AP-1). Life Sci., 2006, 79(26), 2480-2485.
Arcella, A.; Oliva, M.A.; Staffieri, S.; Sanchez, M.; Madonna, M.; Riozzi, B.; Esposito, V.; Giangaspero, F.; Frati, L. Effects of aloe emodin on U87MG glioblastoma cell growth: In vitro and in vivo study. Environ. Toxicol., 2018, 33(11), 1160-1167.
Hurley, R.L.; Anderson, K.A.; Franzone, J.M.; Kemp, B.E.; Means, A.R.; Witters, L.A. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J. Biol. Chem., 2005, 280(32), 29060-29066.
Lee, M.S.; Park, W.S.; Kim, Y.H.; Ahn, W.G.; Kwon, S.H.; Her, S. Intracellular ATP assay of live cells using PTD-conjugated luciferase. Sensors (Basel), 2012, 12(11), 15628-15637.
Miyazaki, N.; Kurihara, K.; Nakano, H.; Shinohara, K. Role of ATP in the sensitivity to heat and the induction of apoptosis in mammalian cells. Int. J. Hyperthermia, 2002, 18(4), 316-331.
Sharma, P.K.; Varshney, R. 2-Deoxy-D-glucose and 6-aminonicotinamide-mediated Nrf2 down regulation leads to radiosensitization of malignant cells via abrogation of GSH-mediated defense. Free Radic. Res., 2012, 46(12), 1446-1457.
Gridley, D.S.; Nutter, R.L.; Mantik, D.W.; Slater, J.M. Hyperthermia and radiation in vivo: Effect of 2-deoxy-D-glucose. Int. J. Radiat. Oncol. Biol. Phys., 1985, 11(3), 567-574.
Tagg, S.L.; Foster, P.A.; Leese, M.P.; Potter, B.V.; Reed, M.J.; Purohit, A.; Newman, S.P. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer. Br. J. Cancer, 2008, 99(11), 1842-1848.
Varshney, R.; Gupta, S.; Dwarakanath, B.S. Radiosensitization of murine Ehrlich ascites tumor by a combination of 2-deoxy-D-glucose and 6-aminonicotinamide. Technol. Cancer Res. Treat., 2004, 3(6), 659-663.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [487 - 501]
Pages: 15
DOI: 10.2174/1871520619666181211121405
Price: $58

Article Metrics

PDF: 19