Synergistic effect of ginsenoside Rg3 with verapamil on the modulation of multidrug resistance in human acute myeloid leukemia cells

Kim,Sung Su; Seong,Sin; Kim,Sung Young

doi:10.3892/ol.2014.1826

Synergistic effect of ginsenoside Rg3 with verapamil on the modulation of multidrug resistance in human acute myeloid leukemia cells

Authors:
- Sung Su Kim
- Sin Seong
- Sung Young Kim
View Affiliations

Affiliations: Department of Oriental Medicine, Kyung Hee University College of Oriental Medicine, Seoul 130‑701, Republic of Korea, Department of Biochemistry, School of Medicine, Konkuk University, Seoul 143‑701, Republic of Korea
Published online on: January 24, 2014 https://doi.org/10.3892/ol.2014.1826
Pages: 1265-1269

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

The pharmacological modulatory effects of 20(S)‑ginsenoside Rg3 (20S‑Rg3) on multidrug resistant cancer cells are reported in the present study. The effects of 20(S)‑Rg3 on the modulation of doxorubicin (DOX) and vincristine (VCR) resistance were examined in the HL60 multidrug resistant subline of human acute myeloid leukemia cells. Results demonstrated that 20S‑Rg3 is as effective as verapamil (Vp) for modulating the high degree primary DOX resistance and low degree VCR cross‑resistance expressed by the H160 cell line. Furthermore, the present study demonstrates for the first time, using isobologram analysis, that the combination of 20S‑Rg3 and Vp enhances the reversal of DOX and VCR resistance in a supra‑additive or at least an additive manner. These results indicate that 20S‑Rg3 may be used as a Vp synergizer or as a promising alternative to Vp in the chemosensitization of multidrug resistant acute myeloid leukemia, with far fewer side effects.

View Figures

View References

1	Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C and Gottesman MM: Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 5:219–234. 2006.
2	Liscovitch M and Lavie Y: Cancer multidrug resistance: a review of recent drug discovery research. IDrugs. 5:349–355. 2002.PubMed/NCBI
3	Kitagawa I, Yoshikawa M, Yoshihara M, Hayashi T and Taniyama T: Chemical studies of crude drugs (1). Constituents of Ginseng radix rubra. Yakugaku Zasshi. 103:612–622. 1983.(In Japanese).
4	Kim SW, Kwon HY, Chi DW, et al: Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg(3). Biochem Pharmacol. 65:75–82. 2003. View Article : Google Scholar : PubMed/NCBI
5	Molnár J, Szabó D, Pusztai R, et al: Membrane associated antitumor effects of crocine-, ginsenoside- and cannabinoid derivates. Anticancer Res. 20:861–867. 2000.PubMed/NCBI
6	Tachikawa E, Kudo K, Nunokawa M, Kashimoto T, Takahashi E and Kitagawa S: Characterization of ginseng saponin ginsenoside-Rg(3) inhibition of catecholamine secretion in bovine adrenal chromaffin cells. Biochem Pharmacol. 62:943–951. 2001. View Article : Google Scholar
7	Jin J, Shahi S, Kang HK, van Veen HW and Fan TP: Metabolites of ginsenosides as novel BCRP inhibitors. Biochem Biophys Res Commun. 345:1308–1314. 2006. View Article : Google Scholar : PubMed/NCBI
8	Marquardt D, McCrone S and Center MS: Mechanisms of multidrug resistance in HL60 cells: detection of resistance-associated proteins with antibodies against synthetic peptides that correspond to the deduced sequence of P-glycoprotein. Cancer Res. 50:1426–1430. 1990.
9	Steel GG and Peckham MJ: Exploitable mechanisms in combined radiotherapy-chemotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys. 5:85–91. 1979. View Article : Google Scholar : PubMed/NCBI
10	Kano Y, Ohnuma T, Okano T and Holland JF: Effects of vincristine in combination with methotrexate and other antitumor agents in human acute lymphoblastic leukemia cells in culture. Cancer Res. 48:351–356. 1988.PubMed/NCBI
11	Kano Y, Suzuki K, Akutsu M, et al: Effects of CPT-11 in combination with other anti-cancer agents in culture. Int J Cancer. 50:604–610. 1992. View Article : Google Scholar : PubMed/NCBI
12	Steel GG: Terminology in the description of drug-radiation interactions. Int J Radiat Oncol Biol Phys. 5:1145–1150. 1979. View Article : Google Scholar : PubMed/NCBI
13	Ford JM and Hait WN: Pharmacologic circumvention of multidrug resistance. Cytotechnology. 12:171–212. 1993. View Article : Google Scholar : PubMed/NCBI
14	Tsuruo T, Iida H, Tsukagoshi S and Sakurai Y: Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res. 41:1967–1972. 1981.PubMed/NCBI
15	Belpomme D, Gauthier S, Pujade-Lauraine E, et al: Verapamil increases the survival of patients with anthracycline-resistant metastatic breast carcinoma. Annal Oncol. 11:1471–1476. 2000. View Article : Google Scholar : PubMed/NCBI
16	Hu XF, Martin TJ, Bell DR, de Luise M and Zalcberg JR: Combined use of cyclosporin A and verapamil in modulating multidrug resistance in human leukemia cell lines. Cancer Res. 50:2953–2957. 1990.
17	Ford JM, Bruggemann EP, Pastan I, Gottesman MM and Hait WN: Cellular and biochemical characterization of thioxanthenes for reversal of multidrug resistance in human and murine cell lines. Cancer Res. 50:1748–1756. 1990.PubMed/NCBI
18	Van de Vrie W, Jonker AM, Marquet RL and Eggermont AM: The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat. J Cancer Res Clin Oncol. 120:533–538. 1994.PubMed/NCBI
19	Lü JM, Yao Q and Chen C: Ginseng compounds: an update on their molecular mechanisms and medical applications. Curr Vasc Pharmacol. 7:293–302. 2009.PubMed/NCBI
20	Park JD, Kim DS, Kwan HY, Son SK, Lee YH, Beak NI, et al: Effects of ginseng saponin on modulation of multidrug resistance. Arch Pharm Res. 19:213–218. 1996. View Article : Google Scholar
21	Jia WW, Bu X, Philips D, et al: Rh2, a compound extracted from ginseng, hypersensitizes multidrug-resistant tumor cells to chemotherapy. Can J Physiol Pharmacol. 82:431–437. 2004. View Article : Google Scholar : PubMed/NCBI
22	Helms S: Cancer prevention and therapeutics: Panax ginseng. Altern Med Rev. 9:259–274. 2004.
23	Yuan HD, Quan HY, Zhang Y, Kim SH and Chung SH: 20(S)-Ginsenoside Rg3-induced apoptosis in HT-29 colon cancer cells is associated with AMPK signaling pathway. Mol Med Rep. 3:825–831. 2010.PubMed/NCBI
24	Jian J, Hu ZF and Huang Y: Effect of ginsenoside Rg3 on Pim-3 and Bad proteins in human pancreatic cancer cell line PANC-1. Ai Zheng. 28:461–465. 2009.(In Chinese).
25	Wang BS, Zhang LS, Song DM, Zhang JH and Liu YM: Effect of gensenoside Rg3 on apoptosis of Hep-2 and expression of HIF-1alpha in human laryngeal cancer cell line under anoxic conditions. Zhong Yao Cai. 32:102–106. 2009.(In Chinese).