Synergistic antitumor effects of combined deguelin and cisplatin treatment in gastric cancer cells

Li,Zhengguang; Wu,Changping; Wu,Jun; Ji,Mei; Shi,Liangrong; Jiang,Jingting; Xu,Bin; Yuan,Jinjin

doi:10.3892/ol.2014.2368

Synergistic antitumor effects of combined deguelin and cisplatin treatment in gastric cancer cells

Authors:
- Zhengguang Li
- Changping Wu
- Jun Wu
- Mei Ji
- Liangrong Shi
- Jingting Jiang
- Bin Xu
- Jinjin Yuan
View Affiliations

Affiliations: Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, P.R. China
Published online on: July 22, 2014 https://doi.org/10.3892/ol.2014.2368
Pages: 1603-1607

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

Deguelin is a naturally occurring rotenoid with marked chemopreventive and antitumor activity. Cisplatin, characterized by damaging DNA, is widely used in the chemotherapy of malignancies, including gastric cancer. The present study investigated whether synergistic effects exist between the combination of deguelin and cisplatin, and the possible mechanism in vitro. The interactive effects of deguelin in combination with various concentrations of cisplatin were evaluated in the human gastric cancer MGC‑803 cell line. The inhibition of cell proliferation was determined by 3‑(4,5)‑dimethylthiazol(‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay and the mechanisms underlying the effects were further evaluated by western blot analysis. The results revealed that the combined treatment of deguelin and cisplatin exhibited a marked inhibition of MGC‑803 cell proliferation when compared with that of the single therapies in vitro. In addition, isobologram analysis revealed that this combined treatment showed a synergistic effect. These observations may have promising therapeutic value for gastric cancer and thus warrant further investigation.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011.
2	Songun I, Putter H, Kranenbarg EM, Sasako M and van de Velde CJ: Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 11:439–449. 2010.
3	Jain VK, Cunningham D and Chau I: Preoperative and postoperative chemotherapy for gastric cancer. Surg Oncol Clin N Am. 21:99–112. 2012.
4	Pasini F, Fraccon AP and DE Manzoni G: The role of chemotherapy in metastatic gastric cancer. Anticancer Res. 31:3543–3554. 2011.
5	Lebwohl D and Canetta R: Clinical development of platinum complexes in cancer therapy: an historical perspective and an update. Eur J Cancer. 34:1522–1534. 1998.
6	Monneret C: Platinum anticancer drugs. From serendipity to rational design. Ann Pharm Fr. 69:286–295. 2011.
7	Kang YK, Kang WK, Shin DB, et al: Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 20:666–673. 2009.
8	Koizumi W, Tanabe S, Saigenji K, et al: Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer. Br J Cancer. 89:2207–2212. 2003.
9	Van Cutsem E, Moiseyenko VM, Tjulandin S, et al; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 24:4991–4997. 2006.
10	Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 355:11–20. 2006.
11	Rennicke A, Voigt W, Mueller T, et al: Resistance mechanisms following cisplatin and oxaliplatin treatment of the human teratocarcinoma cell line 2102EP. Anticancer Res. 25:1147–1155. 2005.
12	Timmer-Bosscha H, Mulder NH and de Vries EG: Modulation of cis-diamminedichloroplatinum(II) resistance: a review. Br J Cancer. 66:227–238. 1992.
13	Chun KH, Kosmeder JW II, Sun S, et al: Effects of deguelin on the phosphatidylinositol 3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells. J Natl Cancer Inst. 95:291–302. 2003.
14	Lee HY, Oh SH, Woo JK, et al: Chemopreventive effects of deguelin, a novel Akt inhibitor, on tobacco-induced lung tumorigenesis. J Natl Cancer Inst. 97:1695–1699. 2005.
15	Murillo G, Salti GI, Kosmeder JW II, Pezzuto JM and Mehta RG: Deguelin inhibits the growth of colon cancer cells through the induction of apoptosis and cell cycle arrest. Eur J Cancer. 38:2446–2454. 2002.
16	Ji BC, Yu CC, Yang ST, et al: Induction of DNA damage by deguelin is mediated through reducing DNA repair genes in human non-small cell lung cancer NCI-H460 cells. Oncol Rep. 27:959–964. 2012.
17	Altaha R, Liang X, Yu JJ and Reed E: Excision repair cross complementing-group 1: gene expression and platinum resistance. Int J Mol Med. 14:959–970. 2004.
18	Choi MK and Kim DD: Platinum transporters and drug resistance. Arch Pharm Res. 29:1067–1073. 2006.
19	Howell SB, Safaei R, Larson CA and Sailor MJ: Copper transporters and the cellular pharmacology of the platinum-containing cancer drugs. Mol Pharmacol. 77:887–894. 2010.
20	Olaussen KA, Mountzios G and Soria JC: ERCC1 as a risk stratifier in platinum-based chemotherapy for nonsmall-cell lung cancer. Curr Opin Pulm Med. 13:284–289. 2007.
21	Saldivar JS, Wu X, Follen M and Gershenson D: Nucleotide excision repair pathway review I: implications in ovarian cancer and platinum sensitivity. Gynecol Oncol. 107(Suppl 1): S56–S71. 2007.
22	Wernyj RP and Morin PJ: Molecular mechanisms of platinum resistance: still searching for the Achilles’ heel. Drug Resist Updat. 7:227–232. 2004.
23	Hou W, Chen L, Yang G, et al: Synergistic antitumor effects of liposomal honokiol combined with adriamycin in breast cancer models. Phytother Res. 22:1125–1132. 2008.
24	Choi KS, Jun JK, Park EC, et al: Performance of different gastric cancer screening methods in Korea: a population-based study. PLoS One. 7:e500412012.
25	Hainsworth JD, Johnson DH and Greco FA: Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol. 10:912–922. 1992.
26	Ohtsu A, Shimada Y, Yoshida S, et al: Phase II study of protracted infusional 5-fluorouracil combined with cisplatinum for advanced gastric cancer: report from the Japan Clinical Oncology Group (JCOG). Eur J Cancer. 30A:2091–2093. 1994.
27	Fuertes MA, Castilla J, Alonso C and Pérez JM: Cisplatin biochemical mechanism of action: from cytotoxicity to induction of cell death through interconnections between apoptotic and necrotic pathways. Curr Med Chem. 10:257–266. 2003.
28	Brabec V: DNA modifications by antitumor platinum and ruthenium compounds: their recognition and repair. Prog Nucleic Acid Res Mol Biol. 71:1–68. 2002.
29	Brabec V and Kasparkova J: Modifications of DNA by platinum complexes. Relation to resistance of tumors to platinum antitumor drugs. Drug Resist Updat. 8:131–146. 2005.
30	Bortul R, Tazzari PL, Billi AM, et al: Deguelin, a PI3K/AKT inhibitor, enhances chemosensitivity of leukaemia cells with an active PI3K/AKT pathway. Br J Haematol. 129:677–686. 2005.