Sequential treatment with ursolic acid chlorophenyl triazole followed by 5-fluorouracil shows synergistic activity in small cell lung cancer cells
Combination therapy has prolonged the survival of patients with small cell lung cancer (SCLC), an aggressive neoplasm characterized by a high rate of metastasis. In the present study the effect of sequential treatment of ursolic acid chlorophenyl triazole (UACT) followed by 5-fluorouracil (5-FU) on human small cell lung cancer cells was investigated. The results revealed a synergistic effect of the sequential treatment with UACT and 5-FUcombination on cytotoxic activities, NF-kB protein activation, repression of TNF-induced NF-kB-dependent reporter gene expression, and TNF-induced COX-2, MMP-9 and Cyclin D1 activation in H209 cells. The synergism in apoptotic cell death was observed in H209, H69, 87-5,and Lu135 cells. The synergistic effect of UACT and 5-FU was observed at a concentration of 50 nM of UACT and 20 µM of 5-FU. These results indicate that UACT and 5-FU combination can be a promising chemotherapeutic regimen in the treatment of SCLC.
Anto RJ, Mukhopadhyay A, Shishodia S, Gairola CG, Aggarwal BB. Cigarette smoke condensate activates nuclear transcription factor-kB through phosphorylation and degradation of IkB?: Correlation with induction of cyclooxygen-ase-2. Carcinogenesis (Lond.) 2002; 23: 1511-18.
Ardizzoni A, Hansen H, Dombernowsky P, et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: A phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol. 1997; 15: 2090-96.
Bai KK, Chen FL, Zhou Y, Zheng YQ, Li YN, Guo YH. Synthesis of [3b-acetoxy-urs-12-en-28-oyl]-1-monoglyceride and investigation on its anti-tumor effects against BGC-823. Bioorg Med Chem. 2011; 19: 4043-50.
Banerjee S, Bueso-Ramos C, Aggarwal BB. Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: Role of nuclear factor, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 2002; 62: 494554.
Choi YH, Baek JH, Yoo MA, Chung HY, Kim ND, Kim KW. Induction of apoptosis by ursolic acid through activation of caspases and down-regulation of c-IAPs in human prostate epithelial cells. Int J Oncol. 2000; 17: 565-71.
Garg A, Aggarwal BB. Nuclear transcription factor-B as a target for cancer drug development. Leukemia (Baltimore) 2002; 16: 1053-68.
Hanna N, Bunn PA Jr, Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006; 24: 2038-43.
Harmand PO, Duval R, Delage C, Simon A. Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and caspase-3 activation in M4Beu melanoma cells. Int J Cancer. 2005; 114: 1-11.
Hsu LY, Kuo PO, Lin CC. Proliferative inhibition, cell-cycle dysregulation and induction of apoptosis by ursolic acid in human non-small cell lung cancer A549 cells. Life Sci. 2004; 75: 2303-16.
Ichinose Y, Yoshimori K, Sakai H, et al. S-1 plus cisplatin combination chemotherapy in patients with advanced non-small cell lung cancer: A multi-institutional phase II trial. Clin Cancer Res. 2004; 10: 7860-64.
Jackman DM, Johnson BE. Small-cell lung cancer. Lancet 2005; 366: 1385-96.
Johnston PG, Lenz HJ, Leichman CG, et al. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 1995; 55: 1407-12.
Kato H, Ichinose Y, Ohta M, et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med. 2004; 350: 1713-21.
Kanjoormana M, Kuttan G. Antiangiogenic activity of ursolic acid. Integr Cancer Ther. 2010; 9: 224-35.
Kawahara M, Furuse K, Segawa Y, et al. Phase II study of S-1, a novel oral fluorouracil, in advanced non-small-cell lung cancer. Br J Cancer. 2001; 85: 939-43.
Kim DK, Baek JH, Kang CM, Yoo MA, Sung JW, Kim DK, Chung HY, Kim ND, Choi YH, Lee SH, Kim KW. Apoptotic activity of ursolic acid may correlate with the inhibition of initiation of DNA replication. Int J Cancer. 2000; 87: 629-36.
Li J, Guo WJ, Yang QY. Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15. World J Gastroenterol. 2002; 8: 493-95.
Ma CM, Cai SQ, Cui JR, Wang RQ, Tu PF, Hattori M, Daneshtalab M. The cytotoxic activity of ursolic acid derivatives. Eur J Med Chem. 2005; 40: 582-89.
Morere JF, Duran A, Tcherakian F, et al. Cisplatin-5-fluorouracil in small cell lung cancer: A phase II study in 109 patients. Lung Cancer. 1994; 11: 275-81.
Matsumoto S, Igishi T, Hashimoto K, et al. Schedule-dependent synergism of vinorelbine and 5-fluorouracil/UACT against non-small cell lung cancer. Int J Oncol. 2004; 25: 1311-18.
Matsushime H, RousselMF, Ashmun RA, Sherr CJ. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 1991; 65: 701-13.
Muto Y, Ninomiya M, Fujiki HJ. Present status of research on cancer chemoprevention in Japan. Japan J Clin Oncol. 1990; 20: 219-24.
Nakagawa M, Tanaka F, Tsubota N, Ohta M, Takao M, Wada H. A randomized phase III trial of adjuvant chemotherapy with UACT for completely resected pathological stage I non-small cell lung cancer: The West Japan Study Group for Lung Cancer Surgery (WJSG)-the 4th study. Ann Oncol. 2005; 16: 75-80.
Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002; 346: 85-91.
Ohe Y, Negoro S, Matsui K, et al. Phase I-II study of amrubicin and cisplatin in previously untreated patients with extensive-stage small-cell lung cancer. Ann Oncol. 2005; 16: 430-36.
Pahl HL. Activators and target genes of Rel/NF-B transcription factors. Oncogene 1999; 18: 6853-66.
Rosti G, Carminati O, Monti M, Tamberi S, Marangolo M. Chemotherapy advances in small cell lung cancer. Ann Oncol. 2006; 5: 99102.
Saraswat B, Visen PK, Agarwal DP. Ursolic acid isolated from Eucalyptus tereticornis protects against ethanol toxicity in isolated rat hepatocytes. Phytother Res. 2000; 14: 163-66.
Sbar EI, Khatri J, Rodman WD, et al. Phase I study of sequential administration of topotecan and 5-fluorouracil in patients with advanced malignancies. Cancer Invest. 2002; 20: 644-50.
Sporn MB, Suh N. Chemoprevention of cancer. Carcinogenesis (Lond.) 2000; 21: 525-30.
Sporn MB, Suh N. Chemoprevention: An essential approach to controlling cancer. Nat Rev Cancer. 2002; 2: 537-43.
Takiuchi H, Ajani JA. Uracil-tegafur in gastric carcinoma: A comprehensive review. J Clin Oncol. 1998; 16: 2877-85.
Wattenberg LW. Inhibition of carcinogenesis by naturally-occurring and synthetic compounds. Basic Life Sci. 1990; 52: 155-66.
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