Ganoderma lucidum derived ganoderenic acid B reverses ABCB1-mediated multidrug resistance in HepG2/ADM cells

Liu,Dao-Lu; Li,Ying-Jie; Yang,Dong-Hua; Wang,Chen-Ran; Xu,Jun; Yao,Nan; Zhang,Xiao-Qi; Chen,Zhe-Sheng; Ye,Wen-Cai; Zhang,Dong-Mei

doi:10.3892/ijo.2015.2925

Ganoderma lucidum derived ganoderenic acid B reverses ABCB1-mediated multidrug resistance in HepG2/ADM cells

Authors:
- Dao-Lu Liu
- Ying-Jie Li
- Dong-Hua Yang
- Chen-Ran Wang
- Jun Xu
- Nan Yao
- Xiao-Qi Zhang
- Zhe-Sheng Chen
- Wen-Cai Ye
- Dong-Mei Zhang
View Affiliations

Affiliations: College of Pharmacy, Jinan University, Guangzhou 510632, P.R. China, Biosample Repository, Core Facility, Fox Chase Cancer Center, Philadelphia, PA, USA, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
Published online on: March 12, 2015 https://doi.org/10.3892/ijo.2015.2925
Pages: 2029-2038

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

Chemotherapy is one of the most common therapeutic option for metastatic tumors and hematological malignancies. ABCB1-mediated multidrug resistance is the major obstacle for chemotherapy. Natural products with diversified structures are ideal source of ABCB1 modulators. Ganoderenic acid B, a lanostane-type triterpene isolated from Ganoderma lucidum, exhibited potent reversal effect on ABCB1-mediated multidrug resistance of HepG2/ADM cells to doxorubicin, vincristine and paclitaxel. Similarly, ganoderenic acid B could also significantly reverse the resistance of ABCB1-overexpressing MCF-7/ADR cells to doxorubicin. Furthermore, ganoderenic acid B notably enhanced intracellular accumulation of rhodamine-123 in HepG2/ADM cells through inhibition of its efflux. ABCB1 siRNA interference assay indicated that the reversal activity of ganoderenic acid B was dependent on ABCB1. Further mechanistic investigations found that ganoderenic acid B did not alter the expression level of ABCB1 and the activity of ABCB1 ATPase. Molecular docking model displayed that the positions of ganoderenic acid B binding to ABCB1 were different from the region of verapamil interacted with ABCB1. Collectively, ganoderenic acid B can enhance the cytotoxicity of chemotherapeutics towards ABCB1-mediated MDR cancer cells via inhibition of the transport function of ABCB1. These findings provide evidence that ganoderenic acid B has the potential to be developed into an ABCB1-mediated multidrug resistance reversal agent.

View Figures

View References

1	Gottesman MM, Fojo T and Bates SE: Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2:48–58. 2002. View Article : Google Scholar : PubMed/NCBI
2	Wu Q, Yang Z, Nie Y, Shi Y and Fan D: Multidrug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett. 347:159–166. 2014. View Article : Google Scholar : PubMed/NCBI
3	Dean M, Hamon Y and Chimini G: The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res. 42:1007–1017. 2001.PubMed/NCBI
4	Breier A, Gibalova L, Seres M, Barancik M and Sulova Z: New insight into p-glycoprotein as a drug target. Anticancer Agents Med Chem. 13:159–170. 2013. View Article : Google Scholar
5	Palmeira A, Sousa E, Vasconcelos MH and Pinto MM: Three decades of P-gp inhibitors: skimming through several generations and scaffolds. Curr Med Chem. 19:1946–2025. 2012. View Article : Google Scholar : PubMed/NCBI
6	Lee CH: Reversing agents for ATP-binding cassette drug transporters. Methods Mol Biol. 596:325–340. 2010. View Article : Google Scholar
7	Wang YS, Liao Z, Li YA, et al: New megastigmane diglycoside from Litsea glutinosa (Lour. ) C B Rob J Brazil Chem Soc. 22:2234–2238. 2011. View Article : Google Scholar
8	Ansari MT, Saify ZS and Sultana N: Malaria and artemisinin derivatives: an updated review. Mini-Rev Med Chem. 13:1879–1902. 2013. View Article : Google Scholar : PubMed/NCBI
9	Sun J, Yeung CA, Co NN, et al: Clitocine reversal of P-glycoprotein associated multi-drug resistance through downregulation of transcription factor NF-κB in R-HepG2 cell line. PLoS One. 7:e407202012. View Article : Google Scholar
10	Zhang DM, Shu C, Chen JJ, et al: BBA, a derivative of 23-hydroxybetulinic acid, potently reverses ABCB1-mediated drug resistance in vitro and in vivo. Mol Pharm. 9:3147–3159. 2012. View Article : Google Scholar : PubMed/NCBI
11	Zhang DM, Li YJ, Shu C, et al: Bipiperidinyl derivatives of 23-hydroxybetulinic acid reverse resistance of HepG2/ADM and MCF-7/ADR cells. Anticancer Drugs. 24:441–454. 2013. View Article : Google Scholar : PubMed/NCBI
12	Yao N, Liu DL, Li YJ, et al: B5H7, a morpholine derivative of 23-hydroxybetulinic acid, reverses doxorubicin resistance in HepG2/ADM. J Cancer Res Updates. 3:59–66. 2014.
13	Liu DL, Li YJ, Yao N, et al: Acerinol, a cyclolanstane triterpenoid from Cimicifuga acerina, reverses ABCB1-mediated multidrug resistance in HepG2/ADM and MCF-7/ADR cells. Eur J Pharmacol. 733:34–44. 2014. View Article : Google Scholar : PubMed/NCBI
14	Wu GS, Guo JJ, Bao JL, et al: Anti-cancer properties of triterpenoids isolated from Ganoderma lucidum (Review). Expert Opin Inv Drug. 22:981–992. 2013. View Article : Google Scholar
15	Guan SH, Xia JM, Yang M, Wang XM, Liu X and Guo DA: Cytotoxic lanostanoid triterpenes from Ganoderma lucidum. J Asian Nat Prod Res. 10:695–700. 2008. View Article : Google Scholar
16	Wu G, Qian Z, Guo J, et al: Ganoderma lucidum extract induces G1 cell cycle arrest, and apoptosis in human breast cancer cells. Am J Chinese Med. 40:631–642. 2002. View Article : Google Scholar
17	Wang J, Chan JY, Fong CC, Tzang CH, Fung KP and Yang M: Transcriptional analysis of doxorubicin-induced cytotoxicity and resistance in human hepatocellular carcinoma cell lines. Liver Int. 129:1338–1347. 2009. View Article : Google Scholar
18	Wu GS, Lu JJ, Gu JJ, et al: Ganoderic acid DM, a natural triterpenoid, induces DNA damage, G1 cell cycle arrest and apoptosis in human breast cancer cells. Fitoterapia. 83:408–414. 2012. View Article : Google Scholar
19	Wang YL, Zhang XQ, Wang GC and Ye WC: Chemical constituents of the fruiting bodies of Ganoderma lucidum. Jiangsu Pharm Clin Res. 14:349–351. 2006.
20	Chan JY, Chu AC, Fung KP, et al: Inhibition of P-glycoprotein expression and reversal of drug resistance of human hepatoma HepG2 cells by multidrug resistance gene (mdr1) antisense RNA. Life Sci. 67:2117–2124. 2000. View Article : Google Scholar : PubMed/NCBI
21	Fu LW, Zhang YM, Liang YJ, Yang XP and Pan QC: The multidrug resistance of tumor cells was reversed by tetrandrine in vitro and in xenografts derived from human breast adenocarcinoma MCF-7/adr cells. Eur J Cancer. 38:418–426. 2002. View Article : Google Scholar : PubMed/NCBI
22	Massart C, Gibassier J, Lucas C, Pourquier P and Robert J: Expression of the MDR1 gene in five human cell lines of medullary thyroid cancer and reversal of the resistance to doxo-rubicine by ciclosporin A and verapamil. B Cancer. 83:39–45. 1996.
23	Aller SG, Yu J, Ward A, et al: Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 323:1718–1722. 2009. View Article : Google Scholar : PubMed/NCBI
24	Sharom FJ: Complex interplay between the P-glycoprotein multidrug efflux pump and the membrane: its role in modulating protein function. Front Oncol. 4:412014. View Article : Google Scholar : PubMed/NCBI
25	Wu CP, Ohnuma S and Ambudkar SV: Discovering natural product modulators to overcome multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol. 12:609–620. 2011. View Article : Google Scholar
26	Li WD, Zhang BD, Wei R, Liu JH and Lin ZB: Reversal effect of Ganoderma lucidum polysaccharide on multidrug resistance in K562/ADM cell line. Acta Pharmacol Sin. 29:620–627. 2008. View Article : Google Scholar : PubMed/NCBI
27	Wang PP, Xu DJ, Huang C, Wang WP and Xu WK: Astragaloside IV reduces the expression level of P-glycoprotein in multidrug-resistant human hepatic cancer cell lines. Mol Med Rep. 9:2131–2137. 2014.PubMed/NCBI
28	Shi Z, Peng XX, Kim IW, et al: Erlotinib (Tarceva, OSI-774) antagonizes ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance. Cancer Res. 67:11012–11022. 2007. View Article : Google Scholar : PubMed/NCBI
29	Mi YJ, Liang YJ, Huang HB, et al: Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-bindingcassette transporters. Cancer Res. 70:7981–7991. 2010. View Article : Google Scholar : PubMed/NCBI
30	Dai CL, Tiwari AK, Wu CP, et al: Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res. 68:7905–7914. 2008. View Article : Google Scholar : PubMed/NCBI
31	Martin C, Berridge G, Mistry P, Higgins C, Charlton P and Callaghan R: The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br J Pharmacol. 128:403–411. 1999. View Article : Google Scholar : PubMed/NCBI
32	Kang MH, Figg WD, Ando Y, et al: The P-glycoprotein antagonist PSC 833 increases the plasma concentrations of 6alpha-hydroxypaclitaxel, a major metabolite of paclitaxel. Clin Cancer Res. 7:1610–1617. 2001.PubMed/NCBI