The blueberry component pterostilbene has potent anti-myeloma activity in bortezomib-resistant cells

Chen,Gege; Xu,Zhijian; Chang,Gaomei; Hou,Jun; Hu,Liangning; Zhang,Yiwen; Yu,Dandan; Li,Bo; Chang,Shuaikang; Xie,Yongsheng; Zhang,Yong; Wei,Rong; Wu,Huiqun; Xiao,Wenqin; Sun,Xi; Tao,Yi; Gao,Lu; Dai,Bojie; Shi,Jumei; Zhu,Weiliang

doi:10.3892/or.2017.5675

The blueberry component pterostilbene has potent anti-myeloma activity in bortezomib-resistant cells

Authors:
- Gege Chen
- Zhijian Xu
- Gaomei Chang
- Jun Hou
- Liangning Hu
- Yiwen Zhang
- Dandan Yu
- Bo Li
- Shuaikang Chang
- Yongsheng Xie
- Yong Zhang
- Rong Wei
- Huiqun Wu
- Wenqin Xiao
- Xi Sun
- Yi Tao
- Lu Gao
- Bojie Dai
- Jumei Shi
- Weiliang Zhu
View Affiliations

Affiliations: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China, CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China, College of Life Science and Technology, Tongji University, Shanghai 200092, P.R. China
Published online on: May 30, 2017 https://doi.org/10.3892/or.2017.5675
Pages: 488-496

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Multiple myeloma (MM) is an incurable hematologic malignancy because of its drug resistance. Pterostilbene (Pter) is found mainly in blueberries and grapes. The effects of Pter and its exact pharmacologic mechanisms on chemoresistant myeloma are not known. Herein, we investigated the anti-myeloma activity of Pter in bortezomib-resistant cell line H929R and explored the related mechanism of action for the first time. We found that Pter inhibited proliferation of H929R cells and promoted apoptosis of the cells through a caspase-dependent pathway, loss of mitochondrial membrane potential, and activation of Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways. DNA damage and S-phase arrest might be involved in Pter-related toxicity in H929R cells. Pter and the histone deacetylase inhibitors panobinostat or vorinostat inhibited proliferation of H929R cells in a synergistic manner. These data supported that Pter might be a promising natural compound for relapsed/refractory myeloma therapy, especially against myeloma resistant to bortezomib chemotherapy.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
2	Anderson KC: The 39th David A. Karnofsky Lecture: Bench-to-bedside translation of targeted therapies in multiple myeloma. J Clin Oncol. 30:445–452. 2012. View Article : Google Scholar : PubMed/NCBI
3	Yang WC and Lin SF: Mechanisms of drug resistance in relapse and refractory multiple myeloma. BioMed Res Int. 2015:3414302015. View Article : Google Scholar : PubMed/NCBI
4	Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, Haessler J, Feather J, Hoering A, Moreau P, et al: International Myeloma Working Group: Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study. Leukemia. 26:149–157. 2012. View Article : Google Scholar : PubMed/NCBI
5	Gupta SC, Kannappan R, Reuter S, Kim JH and Aggarwal BB: Chemosensitization of tumors by resveratrol. Ann NY Acad Sci. 1215:150–160. 2011. View Article : Google Scholar : PubMed/NCBI
6	Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, Nair AS, Shishodia S and Aggarwal BB: Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood. 109:2293–2302. 2007. View Article : Google Scholar : PubMed/NCBI
7	Zhu Y, He W, Gao X, Li B, Mei C, Xu R and Chen H: Resveratrol overcomes gefitinib resistance by increasing the intracellular gefitinib concentration and triggering apoptosis, autophagy and senescence in PC9/G NSCLC cells. Sci Rep. 5:177302015. View Article : Google Scholar : PubMed/NCBI
8	Kato A, Naiki-Ito A, Nakazawa T, Hayashi K, Naitoh I, Miyabe K, Shimizu S, Kondo H, Nishi Y, Yoshida M, et al: Chemopreventive effect of resveratrol and apocynin on pancreatic carcinogenesis via modulation of nuclear phosphorylated GSK3β and ERK1/2. Oncotarget. 6:42963–42975. 2015.PubMed/NCBI
9	Yaseen A, Chen S, Hock S, Rosato R, Dent P, Dai Y and Grant S: Resveratrol sensitizes acute myelogenous leukemia cells to histone deacetylase inhibitors through reactive oxygen species-mediated activation of the extrinsic apoptotic pathway. Mol Pharmacol. 82:1030–1041. 2012. View Article : Google Scholar : PubMed/NCBI
10	Estrela JM, Ortega A, Mena S, Rodriguez ML and Asensi M: Pterostilbene: Biomedical applications. Crit Rev Clin Lab Sci. 50:65–78. 2013. View Article : Google Scholar : PubMed/NCBI
11	McCormack D and McFadden D: Pterostilbene and cancer: Current review. J Surg Res. 173:e53–e61. 2012. View Article : Google Scholar : PubMed/NCBI
12	Chen RJ, Ho CT and Wang YJ: Pterostilbene induces autophagy and apoptosis in sensitive and chemoresistant human bladder cancer cells. Mol Nutr Food Res. 54:1819–1832. 2010. View Article : Google Scholar : PubMed/NCBI
13	Tolomeo M, Grimaudo S, Di Cristina A, Roberti M, Pizzirani D, Meli M, Dusonchet L, Gebbia N, Abbadessa V, Crosta L, et al: Pterostilbene and 3′-hydroxypterostilbene are effective apoptosis-inducing agents in MDR and BCR-ABL-expressing leukemia cells. Int J Biochem Cell Biol. 37:1709–1726. 2005. View Article : Google Scholar : PubMed/NCBI
14	Hollville E and Martin SJ: Measuring apoptosis by microscopy and flow cytometry. Curr Protoc Immunol. 112:1–24. 2016.
15	Koff JL, Ramachandiran S and Bernal-Mizrachi L: A time to kill: Targeting apoptosis in cancer. Int J Mol Sci. 16:2942–2955. 2015. View Article : Google Scholar : PubMed/NCBI
16	Shi Y: Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell. 9:459–470. 2002. View Article : Google Scholar : PubMed/NCBI
17	Fan T-J, Han L-H, Cong RS and Liang J: Caspase family proteases and apoptosis. Acta Biochim Biophys Sin (Shanghai). 37:719–727. 2005. View Article : Google Scholar : PubMed/NCBI
18	Zhu R, Xi H, Li YH, Jiang H, Zou JF and Hou J: Establishment of a bortezomib-resistant myeloma cell line and differential proteins analysis by MALDI-OF-MS. Zhejiang Da Xue Xue Bao Yi Xue Ban. 38:445–452. 2009.(In Chinese). PubMed/NCBI
19	Green DR and Reed JC: Mitochondria and apoptosis. Science. 281:1309–1312. 1998. View Article : Google Scholar : PubMed/NCBI
20	Ni Chonghaile T, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore VG, Deng J, Anderson KC, Richardson P, Tai YT, et al: Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science. 334:1129–1133. 2011. View Article : Google Scholar : PubMed/NCBI
21	Hsiao PC, Chou YE, Tan P, Lee WJ, Yang SF, Chow JM, Chen HY, Lin CH, Lee LM and Chien MH: Pterostilbene simultaneously induced G0/G1-phase arrest and MAPK-mediated mitochondrial-derived apoptosis in human acute myeloid leukemia cell lines. PLoS One. 9:e1053422014. View Article : Google Scholar : PubMed/NCBI
22	Yu W, Chen Y, Xiang R, Xu W, Wang Y, Tong J, Zhang N, Wu Y and Yan H: Novel phosphatidylinositol 3-kinase inhibitor BKM120 enhances the sensitivity of multiple myeloma to bortezomib and overcomes resistance. Leuk Lymphoma. 58:428–437. 2017. View Article : Google Scholar : PubMed/NCBI
23	Bonner WM, Redon CE, Dickey JS, Nakamura AJ, Sedelnikova OA, Solier S and Pommier Y: GammaH2AX and cancer. Nat Rev Cancer. 8:957–967. 2008. View Article : Google Scholar : PubMed/NCBI
24	Chen D, Frezza M, Schmitt S, Kanwar J and Dou QP: Bortezomib as the first proteasome inhibitor anticancer drug: Current status and future perspectives. Curr Cancer Drug Targets. 11:239–253. 2011. View Article : Google Scholar : PubMed/NCBI
25	Murray MY, Auger MJ and Bowles KM: Overcoming bortezomib resistance in multiple myeloma. Biochem Soc Trans. 42:804–808. 2014. View Article : Google Scholar : PubMed/NCBI
26	Reis-Sobreiro M, Gajate C and Mollinedo F: Involvement of mitochondria and recruitment of Fas/CD95 signaling in lipid rafts in resveratrol-mediated antimyeloma and antileukemia actions. Oncogene. 28:3221–3234. 2009. View Article : Google Scholar : PubMed/NCBI
27	Hsieh MJ, Lin CW, Yang SF, Sheu GT, Yu YY, Chen MK and Chiou HL: A combination of pterostilbene with autophagy inhibitors exerts efficient apoptotic characteristics in both chemosensitive and chemoresistant lung cancer cells. Toxicol Sci. 137:65–75. 2014. View Article : Google Scholar : PubMed/NCBI
28	Yang Y, Yan X, Duan W, Yan J, Yi W, Liang Z, Wang N, Li Y, Chen W, Yu S, et al: Pterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cells. PLoS One. 8:e626522013. View Article : Google Scholar : PubMed/NCBI
29	Schneider JG, Alosi JA, McDonald DE and McFadden DW: Effects of pterostilbene on melanoma alone and in synergy with inositol hexaphosphate. Am J Surg. 198:679–684. 2009. View Article : Google Scholar : PubMed/NCBI
30	Ikeda H, Hideshima T, Fulciniti M, Perrone G, Miura N, Yasui H, Okawa Y, Kiziltepe T, Santo L, Vallet S, et al: PI3K/p110{delta} is a novel therapeutic target in multiple myeloma. Blood. 116:1460–1468. 2010. View Article : Google Scholar : PubMed/NCBI
31	Shao X, Lai D, Zhang L and Xu H: Induction of autophagy and apoptosis via PI3K/AKT/TOR pathways by azadirachtin A in Spodoptera litura cells. Sci Rep. 6:354822016. View Article : Google Scholar : PubMed/NCBI
32	Wahl DR and Lawrence TS: Integrating chemoradiation and molecularly targeted therapy. Adv Drug Deliv Rev. 109:74–83. 2017. View Article : Google Scholar : PubMed/NCBI
33	Kastan MB and Bartek J: Cell-cycle checkpoints and cancer. Nature. 432:316–323. 2004. View Article : Google Scholar : PubMed/NCBI
34	Golubnitschaja O: Cell cycle checkpoints: The role and evaluation for early diagnosis of senescence, cardiovascular, cancer, and neurodegenerative diseases. Amino Acids. 32:359–371. 2007. View Article : Google Scholar : PubMed/NCBI
35	Walworth NC: Cell-cycle checkpoint kinases: Checking in on the cell cycle. Curr Opin Cell Biol. 12:697–704. 2000. View Article : Google Scholar : PubMed/NCBI
36	Pietenpol JA and Stewart ZA: Cell cycle checkpoint signaling: Cell cycle arrest versus apoptosis. Toxicology 181–182. 475–481. 2002. View Article : Google Scholar
37	Raedler LA: Farydak (panobinostat): First HDAC inhibitor approved for patients with relapsed multiple myeloma. Am Health Drug Benefits. 9:84–87. 2016.PubMed/NCBI
38	Corrales-Medina FF, Manton CA, Orlowski RZ and Chandra J: Efficacy of panobinostat and marizomib in acute myeloid leukemia and bortezomib-resistant models. Leuk Res. 39:371–379. 2015. View Article : Google Scholar : PubMed/NCBI
39	Maiso P, Carvajal-Vergara X, Ocio EM, López-Pérez R, Mateo G, Gutiérrez N, Atadja P, Pandiella A and San Miguel JF: The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. Cancer Res. 66:5781–5789. 2006. View Article : Google Scholar : PubMed/NCBI
40	Afifi S, Michael A, Azimi M, Rodriguez M, Lendvai N and Landgren O: Role of histone deacetylase inhibitors in relapsed refractory multiple myeloma: A focus on vorinostat and panobinostat. Pharmacotherapy. 35:1173–1188. 2015. View Article : Google Scholar : PubMed/NCBI