Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2

Li,Qiongyu; Wang,Xiangfeng; Shen,Aling; Zhang,Yuchen; Chen,Youqin; Sferra,Thomas  J.; Lin,Jiumao; Peng,Jun

doi:10.3892/etm.2015.2762

Hedyotis diffusa Willd overcomes 5-fluorouracil resistance in human colorectal cancer HCT-8/5-FU cells by downregulating the expression of P-glycoprotein and ATP-binding casette subfamily G member 2

Authors:
- Qiongyu Li
- Xiangfeng Wang
- Aling Shen
- Yuchen Zhang
- Youqin Chen
- Thomas J. Sferra
- Jiumao Lin
- Jun Peng
View Affiliations

Affiliations: Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China, People's Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA
Published online on: September 22, 2015 https://doi.org/10.3892/etm.2015.2762
Pages: 1845-1850

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

Previous studies have demonstrated that Hedyotis diffusa Willd (HDW), a traditional Chinese herbal medicine, exhibits potent anticancer activity in models of colorectal cancer (CRC). Aggressive forms of CRC exhibit resistance to widely used chemotherapeutic drugs, including the antimetabolite, 5‑fluorouracil (5‑FU); however, less is known with regard to the activity of HDW against 5‑FU‑resistant cancer. In the present study, the mechanism of action and the potency of ethanol extracts of HDW (EEHDW) were investigated on a multidrug‑resistant CRC HCT‑8/5‑FU cell line. Using an MTT cell proliferation assay, EEHDW treatment was shown to significantly reduce the cell viability of HCT‑8/5‑FU cells in a dose‑ and time‑dependent manner. Furthermore, EEHDW significantly increased the retention of the ATP‑binding cassette (ABC) transporter substrate, rhodamine‑123, as compared with the untreated controls. To further investigate the molecular mechanisms targeted by EEHDW in the resistant cells, the expression levels of the ABC drug transporter protein, P‑glycoprotein (P‑gp), and ABC subfamily G member 2 (ABCG2), were analyzed using reverse‑transcription polymerase chain reaction and western blot analysis. The mRNA and protein expression levels of P‑gp and ABCG2 were reduced in the HCT‑8/5‑FU cells following EEHDW treatment, indicating that EEHDW inhibits ABCG2‑mediated drug resistance by downregulating the expression of ABCG2 and P‑gp. Therefore, the potential application of EEHDW as a chemotherapeutic adjuvant represents a promising alternative approach to the treatment of drug-resistant CRC.

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. View Article : Google Scholar : PubMed/NCBI
2	Scurr M, Ladell K, Besneux M, et al: Highly prevalent colorectal cancer-infiltrating LAP⁺ Foxp3⁻ T cells exhibit more potent immunosuppressive activity than Foxp3⁺ regulatory T cells. Mucosal Immunol. 7:428–439. 2014. View Article : Google Scholar : PubMed/NCBI
3	Giampieri R, Scartozzi M, Loretelli C, Piva F, Mandolesi A, Lezoche G, Del Prete M, Bittoni A, Faloppi L, Bianconi M, Cecchini L, Guerrieri M, Bearzi I and Cascinu S: Cancer stem cell gene profile as predictor of relapse in high risk stage II and stage III, radically resected colon cancer patients. PLoS One. 8:e728432013. View Article : Google Scholar : PubMed/NCBI
4	Deeley RG, Westlake C and Cole SP: Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev. 86:849–899. 2006. View Article : Google Scholar : PubMed/NCBI
5	Gottesman MM, Fojo T and Bates SE: Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2:48–58. 2008. View Article : Google Scholar
6	Qiao D, Tang S, Aslam S, Ahmad M, To KK, Wang F, Huang Z, Cai J and Fu L: UMMS-4 enhanced sensitivity of chemotherapeutic agents to ABCB1-overexpressing cells via inhibiting function of ABCB1 transporter. Am J Cancer Res. 4:148–160. 2014.PubMed/NCBI
7	Leslie EM, Deeley RG and Cole SP: Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol. 204:216–237. 2005. View Article : Google Scholar : PubMed/NCBI
8	Andersen V, Vogel U, Godiksen S, Frenzel FB, Sæbø M, Hamfjord J, Kure E and Vogel LK: Low ABCB1 gene expression is an early event in colorectal carcinogenesis. PLoS One. 8:e721192013. View Article : Google Scholar : PubMed/NCBI
9	Zhang H, Wang YJ, Zhang YK, Wang DS, Kathawala RJ, Patel A, Talele TT, Chen ZS and Fu LW: AST1306, a potent EGFR inhibitor, antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance. Cancer Lett. 350:61–68. 2014. View Article : Google Scholar : PubMed/NCBI
10	Wang X and Morris ME: Effects of the flavonoid chrysin on nitrofurantoin pharmacokinetics in rats: potential involvement of ABCG2. Drug Metab Dispos. 35:268–274. 2007. View Article : Google Scholar : PubMed/NCBI
11	Robey RW, To KK, Polgar O, Dohse M, Fetsch P, Dean M and Bates SE: ABCG2: A perspective. Adv Drug Deliv Rev. 61:3–13. 2009. View Article : Google Scholar : PubMed/NCBI
12	Li WY, Chan SW, Guo DJ, Chung MK, Leung TY and Yu PH: Water extract of Rheum officinale Baill. induces apoptosis in human lung adenocarcinoma A549 and human breast cancer MCF-7 cell lines. J Ethnopharmacol. 124:251–256. 2009. View Article : Google Scholar : PubMed/NCBI
13	Rasul A, Yu B, Yang LF, Ali M, Khan M, Ma T and Yang H: Induction of mitochondria-mediated apoptosis in human gastric adenocarcinoma SGC-7901 cells by kuraridin and Nor-kurarinone isolated from Sophora flavescens. Asian Pac J Cancer Prev. 12:2499–2504. 2011.PubMed/NCBI
14	Li Q, Sui H, Liu X, Qin JM, Yin PH and Fan ZZ: Effect of Jianpi Jiedu Recipe mediated JNK/SAPK signal transduction pathway on regulating multidrug resistance in human colon carcinoma cells. Zhonghua Zhong Yi Yao Za Zhi. 27:731–735. 2012.(In Chinese).
15	Sadava D, Ahn J, Zhan M, Pang ML, Ding J and Kane SE: Effects of four Chinese herbal extracts on drug-sensitive and multidrug-resistant small-cell lung carcinoma cells. Cancer Chemother Pharmacol. 49:261–266. 2002. View Article : Google Scholar : PubMed/NCBI
16	Xu D, Lu Q and Hu X: Down-regulation of P-glycoprotein expression in MDR breast cancer cell MCF-7/ADR by honokiol. Cancer Lett. 243:274–280. 2006. View Article : Google Scholar : PubMed/NCBI
17	Wan CK, Zhu GY, Shen XL, Chattopadhyay A, Dey S and Fong WF: Gomisin A alters substrate interaction and reverses P-glycoprotein-mediated multidrug resistance in HepG2-DR cells. Biochem Pharmacol. 72:824–837. 2006. View Article : Google Scholar : PubMed/NCBI
18	Liao B, Ge RY, Chen X, Huangfu ZP, Qi Y, Song YP and Wei XD: Synergistic reversal effect of Chinese medicine compound FFJZ combined with cyclosporine A on multidrug resistance of leukemia K562/VCR cell line. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 15:752–755. 2007.(In Chinese). PubMed/NCBI
19	Wang J, Xia Y, Wang H and Hou Z: Chinese herbs of Shenghe Powder reverse multidrug resistance of gastric carcinoma SGC-7901. Integr Cancer Ther. 6:400–404. 2007. View Article : Google Scholar : PubMed/NCBI
20	Hu YJ, Shen XL, Lu HL, Zhang YH, Huang XA, Fu LC and Fong WF: Tenacigenin B derivatives reverse P-glycoprotein-mediated multidrug resistance in HepG2/Dox cells. J Nat Prod. 71:1049–1051. 2008. View Article : Google Scholar : PubMed/NCBI
21	Angelini A, Di Ilio C, Castellani ML, Conti P and Cuccurullo F: Modulation of multidrug resistance p-glycoprotein activity by flavonoids and honokiol in human doxorubicin-resistant sarcoma cells (MES-SA/DX-5): implications for natural sedatives as chemosensitizing agents in cancer therapy. J Biol Regul Homeost Agents. 24:197–205. 2010.PubMed/NCBI
22	Sui H, Liu X, Jin BH, Pan SF, Zhou LH, Yu NA, Wu J, Cai JF, Fan ZZ, Zhu HR and Li Q: Zuo Jin Wan, a traditional Chinese herbal formula, reverses P-gp-mediated MDR in vitro and in vivo. Evid Based Complement Alternat Med. 2013:9570782013.PubMed/NCBI
23	Lin J, Chen Y, Wei L, Chen X, Xu W, Hong Z, Sferra TJ and Peng J: Hedyotis diffusa Willd extract induces apoptosis via activation of the mitochondrion-dependent pathway in human colon carcinoma cells. Int J Oncol. 37:1331–1338. 2010.PubMed/NCBI
24	Lin J, Wei L, Xu W, Hong Z, Liu X and Peng J: Effect of Hedyotis diffusa Willd extract on tumor angiogenesis. Mol Med Rep. 4:1283–1288. 2011.PubMed/NCBI
25	Cai Q, Lin J, Wei L, Zhang L, Wang L, Zhan Y, Zeng J, Xu W, Shen A, Hong Z and Peng J: Hedyotis diffusa Willd inhibits colorectal cancer growth in vivo via inhibition of STAT3 signaling pathway. Int J Mol Sci. 13:6117–6128. 2012. View Article : Google Scholar : PubMed/NCBI
26	Lin J, Wei L, Shen A, Cai Q, Xu W, Li H, Zhan Y, Hong Z and Peng J: Hedyotis diffusa Willd extract suppresses Sonic hedgehog signaling leading to the inhibition of colorectal cancer angiogenesis. Int J Oncol. 42:651–656. 2013. View Article : Google Scholar : PubMed/NCBI
27	Han Y, Bu LM, Ji X, Liu CY and Wang ZH: Modulation of multidrug resistance by andrographolid in a HCT-8/5-FU multidrug-resistant colorectal cancer cell line. Chin J Dig Dis. 6:82–86. 2005. View Article : Google Scholar : PubMed/NCBI
28	Lee JS, Paull K, Alvarez M, Hose C, Monks A, Grever M, Fojo AT and Bates SE: Rhodamine efflux patterns predict P-glycoprotein substrates in the National Cancer Institute drug screen. Mol Pharmacol. 46:627–638. 1994.PubMed/NCBI
29	Twentyman PR, Rhodes T and Rayner S: A comparison of rhodamine 123 accumulation and efflux in cells with P-glycoprotein-mediated and MRP-associated multidrug resistance phenotypes. Eur J Cancer. 30A:1360–1369. 1994. View Article : Google Scholar : PubMed/NCBI
30	Van Cutsem E, Nordlinger B and Cervantes A: ESMO Guidelines Working Group: Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. Ann Oncol. 21(Suppl 5): v93–v97. 2010. View Article : Google Scholar : PubMed/NCBI
31	Natarajan K, Xie Y, Baer MR and Ross DD: Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol. 83:1084–1103. 2012. View Article : Google Scholar : PubMed/NCBI
32	Nakanishi T and Ross DD: Breast cancer resistance protein (BCRP/ABCG2): its role in multidrug resistance and regulation of its gene expression. Chin J Cancer. 31:73–99. 2012. View Article : Google Scholar : PubMed/NCBI
33	Stacy AE, Jansson PJ and Richardson DR: Molecular pharmacology of ABCG2 and its role in chemoresistance. Mol Pharmacol. 84:655–669. 2013. View Article : Google Scholar : PubMed/NCBI
34	Yang HW, Hua MY, Liu HL, Tsai RY, Pang ST, Hsu PH, Tang HJ, Yen TC and Chuang CK: An epirubicin-conjugated nanocarrier with MRI function to overcome lethal multidrug-resistant bladder cancer. Biomaterials. 33:3919–3930. 2012. View Article : Google Scholar : PubMed/NCBI
35	Liu KJ, He JH, Su XD, Sim HM, Xie JD, Chen XG, Wang F, Liang YJ, Singh S, Sodani K, et al: Saracatinib (AZD0530) is a potent modulator of ABCB1-mediated multidrug resistance in vitro and in vivo. Int J Cancer. 132:224–235. 2013. View Article : Google Scholar : PubMed/NCBI
36	Sane R, Mittapalli RK and Elmquist WF: Development and evaluation of a novel microemulsion formulation of elacridar to improve its bioavailability. J Pharm Sci. 102:1343–1354. 2013. View Article : Google Scholar : PubMed/NCBI
37	Kono T, Hata T, Morita S, Munemoto Y, Matsui T, Kojima H, Takemoto H, Fukunaga M, Nagata N, Shimada M, Sakamoto J and Mishima H: Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE): a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of goshajinkigan to prevent oxaliplatin-induced neuropathy. Cancer Chemother Pharmacol. 72:1283–1290. 2013. View Article : Google Scholar : PubMed/NCBI
38	Pallis M and Russell N: A drug efflux independant role for P-glycoprotein in augmenting the apoptosis induced by growth factor withdrawal in acute myeloid leukemia. Br J Haematol. 105:77–83. 1999.