NS-398 enhances the efficacy of bortezomib against RPMI8226 human multiple myeloma cells

Que,Wenzhong; Li,Saiyuan; Chen,Junmin

doi:10.3892/mmr.2013.1394

NS-398 enhances the efficacy of bortezomib against RPMI8226 human multiple myeloma cells

Authors:
- Wenzhong Que
- Saiyuan Li
- Junmin Chen
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Affiliations: Department of Hematology and Rheumatology, The Third Affiliated Hospital of Fujian Medical University, Fuzhou 350003, P.R. China, Department of Pediatrics, The Children’s Hospital of Fuzhou, Fuzhou 350005, P.R. China, Department of Hematology and Rheumatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, P.R. China
Published online on: March 26, 2013 https://doi.org/10.3892/mmr.2013.1394
Pages: 1641-1645

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Abstract

Bortezomib is commonly used in treating multiple myeloma (MM). However, a number of patients develop resistance to bortezomib over time. Cox-2 is overexpressed in MM cells and contributes to apoptosis resistance and MM development. In the present study, RPMI8226 MM cells were treated with the Cox-2 inhibitor NS-398 to investigate whether it enhanced the effect of bortezomib on MM. The results showed that NS-398 and bortezomib acted synergistically to inhibit growth, arrest the cell cycle at the G1 phase and to induce the apoptosis of MM cells. NS-398 inhibited the NF-κB p65 protein levels and the expression of various NF-κB target genes, including cyclin D1, c-Myc, survivin and Bcl-2. In conclusion, NS-398 enhanced the efficacy of bortezomib against MM cells in vitro and this was associated with the inhibition of NF-κB signaling. These findings suggest that the combined use of NS-398 and bortezomib may constitute a promising novel treatment protocol for MM patients.

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1	Merchionne F, Perosa F and Dammacco F: New therapies in multiple myeloma. Clin Exp Med. 7:83–97. 2007. View Article : Google Scholar : PubMed/NCBI
2	Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 348:2609–2617. 2003. View Article : Google Scholar : PubMed/NCBI
3	Hideshima T, Mitsiades C, Akiyama M, et al: Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood. 101:1530–1534. 2003. View Article : Google Scholar : PubMed/NCBI
4	Nencioni A, Grünebach F, Patrone F, et al: Proteasome inhibitors: antitumor effects and beyond. Leukemia. 21:30–36. 2007. View Article : Google Scholar : PubMed/NCBI
5	Markovina S, Callander NS, O’Connor SL, et al: Bortezomib-resistant nuclear factor-kappaB activity in multiple myeloma cells. Mol Cancer Res. 6:1356–1364. 2008. View Article : Google Scholar : PubMed/NCBI
6	Markovina S, Callander NS, O’Connor SL, et al: Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-kappaB activity in myeloma cells. Mol Cancer. 9:1762010. View Article : Google Scholar : PubMed/NCBI
7	Levine L: Proteasome inhibitors: their effects on arachidonic acid release from cells in culture and arachidonic acid metabolism in rat liver cells. BMC Pharmacol. 4:152004. View Article : Google Scholar : PubMed/NCBI
8	Rockwell P, Yuan H, Magnusson R and Figueiredo-Pereira ME: Proteasome inhibition in neuronal cells induces a proinflammatory response manifested by upregulation of cyclooxygenase-2, its accumulation as ubiquitin conjugates, and production of the prostaglandin PGE(2). Arch Biochem Biophys. 374:325–333. 2000. View Article : Google Scholar
9	Mbonye UR, Yuan C, Harris CE, et al: Two distinct pathways for cyclooxygenase-2 protein degradation. J Biol Chem. 283:8611–8623. 2008. View Article : Google Scholar : PubMed/NCBI
10	Voutsadakis IA, Patrikidou A, Tsapakidis K, et al: Additive inhibition of colorectal cancer cell lines by aspirin and bortezomib. Int J Colorectal Dis. 25:795–804. 2010. View Article : Google Scholar : PubMed/NCBI
11	Liu JF, Zhu GJ, Jamieson GG, et al: NS-398 induces apoptosis in human esophageal cancer cells through inhibition of NF-kappaB downstream regulation of cyclooxygenase-2. Cancer Invest. 27:17–23. 2009. View Article : Google Scholar
12	Jin ZJ: Addition in drug combination. Zhongguo Yao Li Xue Bao. 1:70–76. 1980.(In Chinese).
13	Bae SH, Jung ES, Park YM, et al: Expression of cyclooxygenase-2 (COX-2) in hepatocellular carcinoma and growth inhibition of hepatoma cell lines by a COX-2 inhibitor, NS-398. Clin Cancer Res. 7:1410–1418. 2001.PubMed/NCBI
14	Elder DJ, Halton DE, Crew TE and Paraskeva C: Apoptosis induction and cyclooxygenase-2 regulation in human colorectal adenoma and carcinoma cell lines by the cyclooxygenase-2-selective non-steroidal anti-inflammatory drug NS-398. Int J Cancer. 86:553–560. 2000. View Article : Google Scholar : PubMed/NCBI
15	Ladetto M, Vallet S, Trojan A, et al: Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome. Blood. 105:4784–4791. 2005. View Article : Google Scholar : PubMed/NCBI
16	Li QB, Chen ZC, You Y and Zou P: Small interfering RNA of cyclooxygenase-2 induces growth inhibition and apoptosis independently of Bcl-2 in human myeloma RPMI8226 cells. Acta Pharmacol Sin. 28:1031–1036. 2007. View Article : Google Scholar : PubMed/NCBI
17	Ding J, Tsuboi K, Hoshikawa H, et al: Cyclooxygenase isozymes are expressed in human myeloma cells but not involved in anti-proliferative effect of cyclooxygenase inhibitors. Mol Carcinog. 45:250–259. 2006. View Article : Google Scholar : PubMed/NCBI
18	Zhang M, Abe Y, Matsushima T, et al: Selective cyclooxygenase 2 inhibitor NS-398 induces apoptosis in myeloma cells via a Bcl-2 independent pathway. Leuk Lymphoma. 46:425–433. 2005. View Article : Google Scholar : PubMed/NCBI
19	Honjo S, Kase S, Osaki M, et al: COX-2 correlates with F-box protein, Skp2 expression and prognosis in human gastric carcinoma. Int J Oncol. 26:353–360. 2005.PubMed/NCBI
20	Mizutani Y, Nakanishi H, Li YN, et al: Enhanced sensitivity of bladder cancer cells to cisplatin mediated cytotoxicity and apoptosis in vitro and in vivo by the selective cyclooxygenase-2 inhibitor JTE-522. J Urol. 172:1474–1479. 2004. View Article : Google Scholar : PubMed/NCBI
21	Lin J, Hsiao PW, Chiu TH and Chao JI: Combination of cyclooxygenase-2 inhibitors and oxaliplatin increases the growth inhibition and death in human colon cancer cells. Biochem Pharmacol. 70:658–667. 2005. View Article : Google Scholar : PubMed/NCBI
22	Kishimoto Y, Yashima K, Morisawa T, et al: Effects of cyclooxygenase-2 inhibitor NS-398 on APC and c-myc expression in rat colon carcinogenesis induced by azoxymethane. J Gastroenterol. 37:186–193. 2002. View Article : Google Scholar : PubMed/NCBI
23	Hideshima T, Ikeda H, Chauhan D, et al: Bortezomib induces canonical nuclear factor-κB activation in multiple myeloma cells. Blood. 114:1046–1052. 2009.