Emodin alleviates gemcitabine resistance in pancreatic cancer by inhibiting MDR1/P‑glycoprotein and MRPs expression Retraction in /10.3892/ol.2024.14568

Guo,Hongchun; Liu,Feng; Yang,Shuguang; Xue,Tao

doi:10.3892/ol.2020.12030

Emodin alleviates gemcitabine resistance in pancreatic cancer by inhibiting MDR1/P‑glycoprotein and MRPs expression

Retraction in 10.3892/ol.2024.14568

Authors:
- Hongchun Guo
- Feng Liu
- Shuguang Yang
- Tao Xue
View Affiliations

Affiliations: Department of General Surgery, Shanxian Central Hospital, Heze, Shandong 274300, P.R. China, Department of Neurosurgery, Shanxian Central Hospital, Heze, Shandong 274300, P.R. China, Department of Trauma Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: August 27, 2020 https://doi.org/10.3892/ol.2020.12030
Article Number: 167
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Gemcitabine is a gold standard chemotherapeutic agent for pancreatic cancer. However, gemcitabine has limited effectiveness due to the short‑term development of chemoresistance. Emodin, a natural anthraquinone derivative isolated from the roots of rheumatic palm leaves prevents immunosuppression and exerts anticancer effects. The present study aimed to evaluate the effect of emodin on gemcitabine resistance. Gemcitabine‑resistant PANC‑1 pancreatic cancer cell xenografts were established in athymic mice, which were randomly assigned into four treatments groups as follows: Gemcitabine group, Emodin group, Gemcitabine+Emodin group and Negative control group. Body weight, tumor volume and tumor weight were measured over the course of treatment. The effect of each treatment on tumor tissue proliferation and apoptosis from nude mice was evaluated by using immunohistochemistry. The effect of each treatment on the proliferation of gemcitabine‑resistant PANC‑1 cells was also determined by using the Cell Counting Kit‑8. Then, reverse transcription‑quantitative (RT‑q) PCR and western blotting were used to detect the mRNA and protein expression, respectively, of multidrug resistance gene 1 (MDR1) and the drug resistance‑related proteins MRP1 and MRP5. The function and expression level of DR1 gene product, p‑glycoprotein, was also analysed by flow cytometry and RT‑qPCR, respectively. The results demonstrated that the combination of gemcitabine and emodin significantly reduced xenograft volume and reduced tumor growth in mice compared with treatment with gemcitabine or emodin only. In addition, emodin treatment reduced resistance to gemcitabine, which was characterized by the downregulation of P‑glycoprotein, MRP1 and MRP5 expression in the group receiving combination treatment. The level of P‑glycoprotein was also decreased in the group treated with gemcitabine+emodin compared with the single treatment groups. Taken together, these results demonstrated that emodin enhanced gemcitabine efficacy in tumor treatment and alleviated gemcitabine resistance in PANC‑1 cell xenografts in mice via suppressing MDR1/P‑glycoprotein and MRP expression.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2019. CA Cancer J Clin. 69:7–34. 2019. View Article : Google Scholar : PubMed/NCBI
2	Reske SN: PET and PET-CT of malignant tumors of the exocrine pancreas. Radiologe. 49:131–136. 2009.(In German). View Article : Google Scholar : PubMed/NCBI
3	Stathis A and Moore MJ: Advanced pancreatic carcinoma: Current treatment and future challenges. Nat Rev Clin Oncol. 7:163–172. 2010. View Article : Google Scholar : PubMed/NCBI
4	Kim MP and Gallick GE: Gemcitabine resistance in pancreatic cancer: Picking the key players. Clin Cancer Res. 14:1284–1285. 2008. View Article : Google Scholar : PubMed/NCBI
5	Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol. 15:2403–2413. 1997. View Article : Google Scholar : PubMed/NCBI
6	Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D and Sarkar FH: Pancreatic cancer: Understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol. 8:27–33. 2011. View Article : Google Scholar : PubMed/NCBI
7	Arends JJ, Sleeboom HP, Leys MB, Ten Bokkel Huinink D, de Jong RS, Smit JM, Nortier JW and Tesselaar ME: A phase II study of raltitrexed and gemcitabine in patients with advanced pancreatic carcinoma. Br J Cancer. 92:445–448. 2005. View Article : Google Scholar : PubMed/NCBI
8	Hagmann W, Jesnowski R and Löhr JM: Interdependence of gemcitabine treatment, transporter expression, and resistance in human pancreatic carcinoma cells. Neoplasia. 12:740–747. 2010. View Article : Google Scholar : PubMed/NCBI
9	Li HL, Chen HL, Li H, Zhang KL, Chen XY, Wang XW, Kong QY and Liu J: Regulatory effects of emodin on NF-kappaB activation and inflammatory cytokine expression in RAW 264.7 macrophages. Int J Mol Med. 16:41–47. 2005. View Article : Google Scholar : PubMed/NCBI
10	Lin SZ, Chen KJ, Tong HF, Jing H, Li H and Zheng SS: Emodin attenuates acute rejection of liver allografts by inhibiting hepatocellular apoptosis and modulating the Th1/Th2 balance in rats. Clin Exp Pharmacol Physiol. 37:790–794. 2010.PubMed/NCBI
11	Li-Weber M: Targeting apoptosis pathways in cancer by Chinese medicine. Cancer Lett. 332:304–312. 2013. View Article : Google Scholar : PubMed/NCBI
12	Huang Q, Lu G, Shen HM, Chung MC and Ong CN: Anti-cancer properties of anthraquinones from rhubarb. Med Res Rev. 27:609–630. 2007. View Article : Google Scholar : PubMed/NCBI
13	Liu A, Chen H, Wei W, Ye S, Liao W, Gong J, Jiang Z, Wang L and Lin S: Antiproliferative and antimetastatic effects of emodin on human pancreatic cancer. Oncol Rep. 26:81–89. 2011.PubMed/NCBI
14	Liu A, Chen H, Tong H, Ye S, Qiu M, Wang Z, Tan W, Liu J and Lin S: Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB. Mol Med Rep. 4:221–227. 2011.PubMed/NCBI
15	Li J, Liu P, Mao H, Wanga A and Zhang X: Emodin sensitizes paclitaxel-resistant human ovarian cancer cells to paclitaxel-induced apoptosis in vitro. Oncol Rep. 21:1605–1610. 2009.PubMed/NCBI
16	Ko JC, Su YJ, Lin ST, Jhan JY, Ciou SC, Cheng CM and Lin YW: Suppression of ERCC1 and Rad51 expression through ERK1/2 inactivation is essential in emodin-mediated cytotoxicity in human non-small cell lung cancer cells. Biochem Pharmacol. 79:655–664. 2010. View Article : Google Scholar : PubMed/NCBI
17	Chun-Guang W, Jun-Qing Y, Bei-Zhong L, Dan-Ting J, Chong W, Liang Z, Dan Z and Yan W: Anti-tumor activity of emodin against human chronic myelocytic leukemia K562 cell lines in vitro and in vivo. Eur J Pharmacol. 627:33–41. 2010. View Article : Google Scholar : PubMed/NCBI
18	Wang ZH, Chen H, Guo HC, Tong HF, Liu JX, Wei WT, Tan W, Ni ZL, Liu HB and Lin SZ: Enhanced antitumor efficacy by the combination of emodin and gemcitabine against human pancreatic cancer cells via downregulation of the expression of XIAP in vitro and in vivo. Int J Oncol. 39:1123–1131. 2011.PubMed/NCBI
19	Wei WT, Chen H, Ni ZL, Liu HB, Tong HF, Fan L, Liu A, Qiu MX, Liu DL, Guo HC, et al: Antitumor and apoptosis-promoting properties of emodin, an anthraquinone derivative from Rheum officinale Baill, against pancreatic cancer in mice via inhibition of Akt activation. Int J Oncol. 39:1381–1390. 2011.PubMed/NCBI
20	Kusuhara H and Sugiyama Y: Role of transporters in the tissue-selective distribution and elimination of drugs: Transporters in the liver, small intestine, brain and kidney. J Control Release. 78:43–54. 2002. View Article : Google Scholar : PubMed/NCBI
21	Lee CA, Cook JA, Reyner EL and Smith DA: P-glycoprotein related drug interactions: Clinical importance and a consideration of disease states. Expert Opin Drug Metab Toxicol. 6:603–619. 2010. View Article : Google Scholar : PubMed/NCBI
22	O'Driscoll L, Walsh N, Larkin A, Ballot J, Ooi WS, Gullo G, O'Connor R, Clynes M, Crown J and Kennedy S: MDR1/P-glycoprotein and MRP-1 drug efflux pumps in pancreatic carcinoma. Anticancer Res. 27:2115–2120. 2007.PubMed/NCBI
23	Leonessa F and Clarke R: ATP binding cassette transporters and drug resistance in breast cancer. Endocr Relat Cancer. 10:43–73. 2003. View Article : Google Scholar : PubMed/NCBI
24	Yu Y, Ding F, Gao M, Jia YF and Ren L: Establishment and characterization of the gemcitabine-resistant human pancreatic cancer cell line SW1990/gemcitabine. Oncol Lett. 18:3065–3071. 2019.PubMed/NCBI
25	Lou C, Lu H, Ma Z, Liu C and Zhang Y: Ginkgolide B enhances gemcitabine sensitivity in pancreatic cancer cell lines via inhibiting PAFR/NF-κB pathway. Biomed Pharmacother. 109:563–572. 2019. View Article : Google Scholar : PubMed/NCBI
26	Kong R, Sun B, Jiang H, Pan S, Chen H, Wang S, Krissansen GW and Sun X: Downregulation of nuclear factor-kappaB p65 subunit by small interfering RNA synergizes with gemcitabine to inhibit the growth of pancreatic cancer. Cancer Lett. 291:90–98. 2010. View Article : Google Scholar : PubMed/NCBI
27	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
28	Shain KH and Dalton WS: Cell adhesion is a key determinant in de novo multidrug resistance (MDR): New targets for the prevention of acquired MDR. Mol Cancer Ther. 1:69–78. 2001.PubMed/NCBI
29	Schinkel AH and Jonker JW: Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: An overview. Adv Drug Deliv Rev. 55:3–29. 2003. View Article : Google Scholar : PubMed/NCBI
30	Takakuwa O, Oguri T, Ozasa H, Uemura T, Kasai D, Miyazaki M, Maeno K and Sato S: Over-expression of MDR1 in amrubicinol-resistant lung cancer cells. Cancer Chemother Pharmacol. 68:669–676. 2011. View Article : Google Scholar : PubMed/NCBI
31	Konig J, Hartel M, Nies AT, Martignoni ME, Guo J, Büchler MW, Friess H and Keppler D: Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. Int J Cancer. 115:359–367. 2005. View Article : Google Scholar : PubMed/NCBI
32	Noma B, Sasaki T, Fujimoto Y, Serikawa M, Kobayashi K, Inoue M, Itsuki H, Kamigaki M, Minami T and Chayama K: Expression of multidrug resistance-associated protein 2 is involved in chemotherapy resistance in human pancreatic cancer. Int J Oncol. 33:1187–1194. 2008.PubMed/NCBI