Open Access

Treatment with 20(S)-ginsenoside Rg3 reverses multidrug resistance in A549/DDP xenograft tumors

  • Authors:
    • Chao Liu
    • Quan Gong
    • Ting Chen
    • Juan Lv
    • Zhiping Feng
    • Pengjie Liu
    • Zhiyong Deng
  • View Affiliations

  • Published online on: January 24, 2018     https://doi.org/10.3892/ol.2018.7849
  • Pages: 4376-4382
  • Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Multidrug resistance (MDR) is an obstacle for cancer chemotherapy. It was reported that 20(S)-ginsenoside Rg3 (hereafter Rg3) was able to regulate MDR in mouse leukemia cells. The present study investigated the effect of Rg3 on the MDR of A549 lung cancer cells. A cell viability assay revealed that Rg3 treatment increased cisplatin (DDP) cytotoxicity in DDP resistant A549 cells (A549/DDP). Furthermore, Rg3 increases the antitumor effect of DDP on A549/DDP xenograft mice. The expression of MDR‑mediated proteins, including P‑glycoprotein (P‑gp), multidrug resistance‑associated protein (MPR1) and lung resistance protein 1 (LPR1), was detected in tumor tissue of A549/DDP xenograft mice. The results revealed that Rg3 treatment inhibited the expression of these MDR‑associated proteins. Additionally, technetium‑99m labeled hexakis-2-methoxyisobutylisonitrile (99mTc‑MIBI) single‑photon emission computed tomography was used to monitor the effect of Rg3 on cisplatin sensitivity of A549/DDP xenograft tumors. It was observed that uptake of 99mTc‑MIBI was increased by Rg3 treatment, which indicated that Rg3 is able to effectively enhance chemotherapy sensitivity of A549/DDP xenograft tumors. Taken together, these results revealed that Rg3 may be able to reverse MDR of lung cancer via the downregulation of P‑gp, MPR1 and LPR1.

References

1 

Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI

2 

She J, Yang P, Hong Q and Bai C: Lung cancer in China: Challenges and interventions. Chest. 143:1117–1126. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Thatcher N and Heighway J: Maintenance and consolidation therapy in patients with unresectable stage III/IV non-small cell lung cancer. Oncologist. 15:1034–1042. 2010. View Article : Google Scholar : PubMed/NCBI

4 

Sereno M, Rodriguez-Esteban I, Gómez-Raposo C, Merino M, López-Gómez M, Zambrana F and Casado E: Lung cancer and peritoneal carcinomatosis. Oncol Lett. 6:705–708. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Hellmann MD, Li BT, Chaft JE and Kris MG: Chemotherapy remains an essential element of personalized care for persons with lung cancers. Ann Oncol. 27:1829–1835. 2016. View Article : Google Scholar : PubMed/NCBI

6 

Wang J, Zhang J, Zhang L, Zhao L, Fan S, Yang Z, Gao F, Kong Y, Xiao GG and Wang Q: Expression of P-gp, MRP, LRP, GST-pi and TopoIIalpha and intrinsic resistance in human lung cancer cell lines. Oncol Rep. 26:1081–1089. 2011.PubMed/NCBI

7 

Wang XS, Zhang YJ, Liu XL, Zhou ZR, Hu CS and Eisbruch A: The role of technetium-99m methoxyisobutyl isonitrile scintigraphy in predicting the therapeutic effect of chemotherapy against nasopharyngeal carcinoma. Cancer. 117:2435–2441. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Kim SS, Seong S and Kim SY: Synergistic effect of ginsenoside Rg3 with verapamil on the modulation of multidrug resistance in human acute myeloid leukemia cells. Oncol Lett. 7:1265–1269. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Kwon HY, Kim EH, Kim SW, Kim SN, Park JD and Rhee DK: Selective toxicity of ginsenoside Rg3 on multidrug resistant cells by membrane fluidity modulation. Arch Pharm Res. 31:171–177. 2008. View Article : Google Scholar : PubMed/NCBI

10 

Sadava D and Kane SE: Silibinin reverses drug resistance in human small-cell lung carcinoma cells. Cancer Lett. 339:102–106. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Gottesman MM, Fojo T and Bates SE: Multidrug resistance in cancer: Role of ATP-dependent transporters. Nature Rev Cancer. 2:48–58. 2002. View Article : Google Scholar

12 

Sharom FJ: The P-glycoprotein multidrug transporter. Essays Biochem. 50:161–178. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Polgar O and Bates SE: ABC transporters in the balance: Is there a role in multidrug resistance? Biochem Soc Trans. 33:241–245. 2005. View Article : Google Scholar : PubMed/NCBI

14 

Steinbach D and Legrand O: ABC transporters and drug resistance in leukemia: Was P-gp nothing but the first head of the Hydra? Leukemia. 21:1172–1176. 2007. View Article : Google Scholar : PubMed/NCBI

15 

Zhu WY, Hunag YY, Liu XG, He JY, Chen DD, Zeng F, Zhou JH and Zhang YK: Prognostic evaluation of CapG, gelsolin, P-gp, GSTP1 and Topo-II proteins in non-small cell lung cancer. Anat Rec (Hoboken). 295:208–214. 2012. View Article : Google Scholar : PubMed/NCBI

16 

Borst P, Evers R, Kool M and Wijnholds J: A family of drug transporters: The multidrug resistance-associated proteins. J Natl Cancer Inst. 92:1295–1302. 2000. View Article : Google Scholar : PubMed/NCBI

17 

Scheffer GL, Wijngaard PL, Flens MJ, Izquierdo MA, Slovak ML, Pinedo HM, Meijer CJ, Clevers HC and Scheper RJ: The drug resistance-related protein LRP is the human major vault protein. Nat Med. 1:578–582. 1995. View Article : Google Scholar : PubMed/NCBI

18 

Attele AS, Wu JA and Yuan CS: Ginseng pharmacology: Multiple constituents and multiple actions. Biochem Pharmacol. 58:1685–1693. 1999. View Article : Google Scholar : PubMed/NCBI

19 

Gillis CN: Panax ginseng pharmacology: A nitric oxide link? Biochem Pharmacol. 54:1–8. 1997. View Article : Google Scholar : PubMed/NCBI

20 

Molnar J, Szabo D, Pusztai R, Mucsi I, Berek L, Ocsovszki I, Kawata E and Shoyama Y: Membrane associated antitumor effects of crocine-, ginsenoside- and cannabinoid derivates. Anticancer Res. 20:861–867. 2000.PubMed/NCBI

21 

Geng L, Fan J, Gao QL, Yu J and Hua BJ: Preliminary study for the roles and mechanisms of 20(R)-ginsenoside Rg3 and PEG-PLGA-Rg3 nanoparticles in the Lewis lung cancer mice. Beijing Da Xue Xue Bao Yi Xue Ban. 48:496–501. 2016.(In Chinese). PubMed/NCBI

22 

Zhang F, Li M, Wu X, Hu Y, Cao Y, Wang X, Xiang S, Li H, Jiang L, Tan Z, et al: 20(S)-ginsenoside Rg3 promotes senescence and apoptosis in gallbladder cancer cells via the p53 pathway. Drug Des Devel Ther. 9:3969–3987. 2015.PubMed/NCBI

23 

Cheong JH, Kim H, Hong MJ, Yang MH, Kim JW, Yoo H, Yang H, Park JH, Sung SH, Kim HP and Kim J: Stereoisomer-specific anticancer activities of ginsenoside Rg3 and Rh2 in HepG2 cells: Disparity in cytotoxicity and autophagy-inducing effects due to 20(S)-epimers. Biol Pharm Bull. 38:102–108. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Liu T, Zhao L, Zhang Y, Chen W, Liu D, Hou H, Ding L and Li X: Ginsenoside 20(S)-Rg3 targets HIF-1α to block hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells. PLoS One. 9:e1038872014. View Article : Google Scholar : PubMed/NCBI

25 

Kim SW, Kwon HY, Chi DW, Shim JH, Park JD, Lee YH, Pyo S and Rhee DK: Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg (3). Biochem Pharmacol. 65:75–82. 2003. View Article : Google Scholar : PubMed/NCBI

26 

Zhu W, Xu H, Zhu D, Zhi H, Wang T, Wang J, Jiang B, Shu Y and Liu P: miR-200bc/429 cluster modulates multidrug resistance of human cancer cell lines by targeting BCL2 and XIAP. Cancer Chemother Pharmacol. 69:723–731. 2012. View Article : Google Scholar : PubMed/NCBI

27 

Yamaue H, Tanimura H, Noguchi K, Hotta T, Tani M, Tsunoda T, Iwahashi M, Tamai M and Iwakura S: Chemosensitivity testing of fresh human gastric cancer with highly purified tumour cells using the MTT assay. Br J Cancer. 66:794–799. 1992. View Article : Google Scholar : PubMed/NCBI

28 

Loening AM and Gambhir SS: AMIDE: A free software tool for multimodality medical image analysis. Mol Imaging. 2:131–137. 2003. View Article : Google Scholar : PubMed/NCBI

29 

Duan XY, Wang JS, Liu M and Guo YM: Technetium-99m-hexakis-2-methoxyisobutylisonitrile scintigraphy and multidrug resistance-related protein expression in human primary lung cancer. Ann Nucl Med. 22:49–55. 2008. View Article : Google Scholar : PubMed/NCBI

30 

Wang H, Wang L, Song L, Zhang YW, Ye J, Xu RX, Shi N and Meng XM: TNNI3K is a novel mediator of myofilament function and phosphorylates cardiac troponin I. Braz J Med Biol Res. 46:128–137. 2013. View Article : Google Scholar : PubMed/NCBI

31 

Wang L, Wang H, Ye J, Xu RX, Song L, Shi N, Zhang YW, Chen X and Meng XM: Adenovirus-mediated overexpression of cardiac troponin I-interacting kinase promotes cardiomyocyte hypertrophy. Clin Exp Pharmacol Physiol. 38:278–284. 2011. View Article : Google Scholar : PubMed/NCBI

32 

Gao Y, Li W, Liu X, Gao F and Zhao X: Reversing effect and mechanism of soluble resistance-related calcium-binding protein on multidrug resistance in human lung cancer A549/DDP cells. Mol Med Rep. 11:2118–2124. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Wang H, Chen Y, Lu XA, Liu G, Fu Y and Luo Y: Endostatin prevents dietary-induced obesity by inhibiting adipogenesis and angiogenesis. Diabetes. 64:2442–2456. 2015. View Article : Google Scholar : PubMed/NCBI

34 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

35 

Zhou W and Christiani DC: East meets west: Ethnic differences in epidemiology and clinical behaviors of lung cancer between East Asians and caucasians. Chin J Cancer. 30:287–292. 2011. View Article : Google Scholar : PubMed/NCBI

36 

Li K, Chen B, Xu L, Feng J, Xia G, Cheng J, Wang J, Gao F and Wang X: Reversal of multidrug resistance by cisplatin-loaded magnetic Fe3O4 nanoparticles in A549/DDP lung cancer cells in vitro and in vivo. Int J Nanomedicine. 8:1867–1877. 2013.PubMed/NCBI

37 

Yan LH, Wei WY, Cao WL, Zhang XS, Xie YB and Xiao Q: Overexpression of E2F1 in human gastric carcinoma is involved in anti-cancer drug resistance. BMC Cancer. 14:9042014. View Article : Google Scholar : PubMed/NCBI

38 

Kang JH, Lee SI, Lim DH, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, et al: Salvage chemotherapy for pretreated gastric cancer: A randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 30:1513–1518. 2012. View Article : Google Scholar : PubMed/NCBI

39 

Montagnani F, Turrisi G, Marinozzi C, Aliberti C and Fiorentini G: Effectiveness and safety of oxaliplatin compared to cisplatin for advanced, unresectable gastric cancer: A systematic review and meta-analysis. Gastric Cancer. 14:50–55. 2011. View Article : Google Scholar : PubMed/NCBI

40 

Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y and Fukuoka M: Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm cooperative study in Japan. Ann Oncol. 18:317–323. 2007. View Article : Google Scholar : PubMed/NCBI

41 

Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J, Vernes JM, Jiang Z, Meng YG, Peale FV, et al: An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med. 19:1114–1123. 2013. View Article : Google Scholar : PubMed/NCBI

42 

Kawakami M, Nakamura T, Okamura N, Komoto C, Markova S, Kobayashi H, Hashimoto N, Okumura K and Sakaeda T: Knock-down of sorcin induces up-regulation of MDR1 in HeLa cells. Biol Pharm Bull. 30:1065–1073. 2007. View Article : Google Scholar : PubMed/NCBI

43 

Akazawa Y, Kawaguchi H, Funahashi M, Watanabe Y, Yamaoka K, Hashida M and Takakura Y: Effect of interferons on P-glycoprotein-mediated rhodamine-123 efflux in cultured rat hepatocytes. J Pharm Sci. 91:2110–2115. 2002. View Article : Google Scholar : PubMed/NCBI

44 

Toner AP, McLaughlin F, Giles FJ, Sullivan FJ, O'Connell E, Carleton LA, Breen L, Dunne G, Gorman AM, Lewis JD and Glynn SA: The novel toluidine sulphonamide EL102 shows pre-clinical in vitro and in vivo activity against prostate cancer and circumvents MDR1 resistance. Br J Cancer. 109:2131–2141. 2013. View Article : Google Scholar : PubMed/NCBI

45 

Tajitsu Y, Ikeda R, Nishizawa Y, Mataki H, Che XF, Sumizawa T, Nitta M, Yamaguchi T, Yamamoto M, Tabata S, et al: Molecular basis for the expression of major vault protein induced by hyperosmotic stress in SW620 human colon cancer cells. Int J Mol Med. 32:703–708. 2013. View Article : Google Scholar : PubMed/NCBI

46 

Keppler D: Multidrug resistance proteins (MRPs, ABCCs): Importance for pathophysiology and drug therapy. Handb Exp Pharmacol. 1–323. 2011.

47 

Tognon G, Bernasconi S, Celli N, Faircloth GT, Cuevas C, Jimeno J, Erba E and D'Incalci M: Induction of resistance to Aplidin in a human ovarian cancer cell line related to MDR expression. Cancer Biol Ther. 4:1325–1330. 2005. View Article : Google Scholar : PubMed/NCBI

48 

Jin L, Xu M, Luo XH and Zhu XF: Stephania tetrandra and ginseng-containing chinese herbal formulation NSENL reverses cisplatin resistance in lung cancer xenografts. Am J Chin Med. 45:385–401. 2017. View Article : Google Scholar : PubMed/NCBI

49 

Mubashar M, Harrington KJ, Chaudhary KS, Lalani el-N, Stamp GW, Sinnett D, Glass DM and Peters AM: 99mTc-sestamibi imaging in the assessment of toremifene as a modulator of multidrug resistance in patients with breast cancer. J Nucl Med. 43:519–525. 2002.PubMed/NCBI

50 

Saggiorato E, Angusti T, Rosas R, Martinese M, Finessi M, Arecco F, Trevisiol E, Bergero N, Puligheddu B, Volante M, et al: 99mTc-MIBI imaging in the presurgical characterization of thyroid follicular neoplasms: Relationship to multidrug resistance protein expression. J Nucl Med. 50:1785–1793. 2009. View Article : Google Scholar : PubMed/NCBI

51 

Piwnica-Worms D, Chiu ML, Budding M, Kronauge JF, Kramer RA and Croop JM: Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex. Cancer Res. 53:977–984. 1993.PubMed/NCBI

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April 2018
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Copy and paste a formatted citation
APA
Liu, C., Gong, Q., Chen, T., Lv, J., Feng, Z., Liu, P., & Deng, Z. (2018). Treatment with 20(S)-ginsenoside Rg3 reverses multidrug resistance in A549/DDP xenograft tumors. Oncology Letters, 15, 4376-4382. https://doi.org/10.3892/ol.2018.7849
MLA
Liu, C., Gong, Q., Chen, T., Lv, J., Feng, Z., Liu, P., Deng, Z."Treatment with 20(S)-ginsenoside Rg3 reverses multidrug resistance in A549/DDP xenograft tumors". Oncology Letters 15.4 (2018): 4376-4382.
Chicago
Liu, C., Gong, Q., Chen, T., Lv, J., Feng, Z., Liu, P., Deng, Z."Treatment with 20(S)-ginsenoside Rg3 reverses multidrug resistance in A549/DDP xenograft tumors". Oncology Letters 15, no. 4 (2018): 4376-4382. https://doi.org/10.3892/ol.2018.7849