Rubus coreanus Miquel extract causes apoptosis of doxorubicin-resistant NCI/ADR-RES ovarian cancer cells via JNK phosphorylation

Kim,Min  Kyoung; Choi,Hyeong  Sim; Cho,Sung‑Gook; Shin,Yong  Cheol; Ko,Seong‑Gyu

doi:10.3892/mmr.2016.4996

Rubus coreanus Miquel extract causes apoptosis of doxorubicin-resistant NCI/ADR-RES ovarian cancer cells via JNK phosphorylation

Authors:
- Min Kyoung Kim
- Hyeong Sim Choi
- Sung‑Gook Cho
- Yong Cheol Shin
- Seong‑Gyu Ko
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Affiliations: Department of Preventive Medicine, College of Korean Medicine, Kyung Hee University, Seoul 130‑701, Republic of Korea, Department of Biotechnology, Korea National University of Transportation, Jeungpyeong‑gun, Chungbuk 368‑701, Republic of Korea
Published online on: March 17, 2016 https://doi.org/10.3892/mmr.2016.4996
Pages: 4065-4072

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Abstract

Cancer cells can acquire an anticancer, drug-resistant phenotype following chemotherapy, which is tightly linked to cancer malignancy and patient survival rates. Therefore, the identification of options to treat chemotherapy‑resistant cancer cells is an urgent requirement. Rubus coreanus Miquel (RCM) has long been used as a source of food. In addition, it has been reported that RCM has effective functions against particular diseases, including cancer and inflammation. In the present study, it was demonstrated that RCM extract caused the apoptotic cell death of doxorubicin‑resistant NCI/ADR‑RES ovarian cancer cells by phosphorylating c‑Jun N‑terminal kinase (JNK). The RCM‑mediated reduction of cell viability showed no synergism with doxorubicin. In addition, ellagic acid and quercetin, which are phytochemicals found in RCM, also caused apoptosis of the NCI/ADR‑RES cells. In subsequent investigations of the RCM‑altered signaling pathway, RCM extract, ellagic acid and quercetin were found to commonly induce the phosphorylation of JNK and AKT. Additionally, the inhibition of JNK with SP600125 repressed the apoptotic cell death induced by RCM extract, ellagic acid and quercetin, and the inhibition of JNK appeared to switch apoptosis to necrosis. JNK inhibition also reduced the phosphorylation of AKT, which was induced by RCM extract, ellagic acid and quercetin, suggesting that the phosphorylation of JNK is required for AKT phosphorylation in RCM‑, ellagic acid‑ or quercetin‑induced apoptotic cell death. Therefore, the data obtained in the present study led to the conclusion that RCM caused apoptosis of doxorubicin‑resistant NCI/ADR-RES ovarian cancer cells via JNK phosphorylation, and suggested that RCM may be effective in the treatment of chemotherapy‑resistant cancer cells.

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1	Obenauf AC, Zou Y, Ji AL, Vanharanta S, Shu W, Shi H, Kong X, Bosenberg MC, Wiesner T, Rosen N, et al: Therapy-induced tumour secretomes promote resistance and tumour progression. Nature. 520:368–372. 2015. View Article : Google Scholar : PubMed/NCBI
2	Fu F, Nowak MA and Bonhoeffer S: Spatial heterogeneity in drug concentrations can facilitate the emergence of resistance to cancer therapy. PLoS Comput Biol. 11:e10041422015. View Article : Google Scholar : PubMed/NCBI
3	Oshimori N, Oristian D and Fuchs E: TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell. 160:963–976. 2015. View Article : Google Scholar : PubMed/NCBI
4	Borst P: Cancer drug pan-resistance: Pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what? Open Biol. 2:1200662012. View Article : Google Scholar : PubMed/NCBI
5	Meng F and Wu G: The rejuvenated scenario of epithelial-mesenchymal transition (EMT) and cancer metastasis. Cancer Metastasis Rev. 31:455–467. 2012. View Article : Google Scholar : PubMed/NCBI
6	Singh A and Settleman J: EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene. 29:4741–4751. 2010. View Article : Google Scholar : PubMed/NCBI
7	Matsumoto K, Onda T and Yaegashi N: Pharmacotherapy for recurrent ovarian cancer: Current status and future perspectives. Jpn J Clin Oncol. 45:408–410. 2015. View Article : Google Scholar : PubMed/NCBI
8	Jung KA, Han D, Kwon EK, Lee CH and Kim YE: Antifatigue effect of Rubus coreanus Miquel extract in mice. J Med Food. 10:689–693. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kim Y, Kim J, Lee SM, Lee HA, Park S, Kim Y and Kim JH: Chemopreventive effects of Rubus coreanus Miquel on prostate cancer. Biosci Biotechnol Biochem. 76:737–744. 2012. View Article : Google Scholar : PubMed/NCBI
10	Choi C, Lee H, Lim H, Park S, Lee J and Do S: Effect of Rubus coreanus extracts on diabetic osteoporosis by simultaneous regulation of osteoblasts and osteoclasts. Menopause. 19:1043–1051. 2012. View Article : Google Scholar : PubMed/NCBI
11	Kim SK, Kim H, Kim SA, Park HK and Kim W: Anti-inflammatory and anti-superbacterial activity of polyphenols isolated from black raspberry. Korean J Physiol Pharmacol. 17:73–79. 2013. View Article : Google Scholar : PubMed/NCBI
12	Im SE, Nam TG, Lee H, Han MW, Heo HJ, Koo SI, Lee CY and Kim DO: Anthocyanins in the ripe fruits of Rubus coreanus Miquel and their protective effect on neuronal PC-12 cells. Food Chem. 139:604–610. 2013. View Article : Google Scholar : PubMed/NCBI
13	Chae HJ, Yim JE, Kim KA and Chyun JH: Hepatoprotective effects of Rubus coreanus miquel concentrates on liver injuries induced by carbon tetrachloride in rats. Nutr Res Pract. 8:40–45. 2014. View Article : Google Scholar : PubMed/NCBI
14	Choi MR, Lee MY, Hong JE, Kim JE, Lee JY, Kim TH, Chun JW, Shin HK and Kim EJ: Rubus coreanus Miquel ameliorates scopolamine-induced memory impairments in ICR mice. J Med Food. 17:1049–1056. 2014. View Article : Google Scholar : PubMed/NCBI
15	Kim Y, Lee SM and Kim JH: Unripe Rubus coreanus Miquel suppresses migration and invasion of human prostate cancer cells by reducing matrix metalloproteinase expression. Biosci Biotechnol Biochem. 78:1402–1411. 2014. View Article : Google Scholar : PubMed/NCBI
16	Shin JS, Cho EJ, Choi HE, Seo JH, An HJ, Park HJ, Cho YW and Lee KT: Anti-inflammatory effect of a standardized triterpenoid-rich fraction isolated from Rubus coreanus on dextran sodium sulfate-induced acute colitis in mice and LPS-induced macrophages. J Ethnopharmacol. 158:291–300. 2014. View Article : Google Scholar : PubMed/NCBI
17	Basu A, Nguyen A, Betts NM and Lyons TJ: Strawberry as a functional food: An evidence-based review. Crit Rev Food Sci Nutr. 54:790–806. 2014. View Article : Google Scholar
18	Zhang HM, Zhao L, Li H, Xu H, Chen WW and Tao L: Research progress on the anticarcinogenic actions and mechanisms of ellagic acid. Cancer Biol Med. 11:92–100. 2014.PubMed/NCBI
19	Miles SL, McFarland M and Niles RM: Molecular and physiological actions of quercetin: Need for clinical trials to assess its benefits in human disease. Nutr Rev. 72:720–734. 2014. View Article : Google Scholar : PubMed/NCBI
20	Liscovitch M and Ravid D: A case study in misidentification of cancer cell lines: MCF-7/AdrR cells (re-designated NCI/ADR-RES) are derived from OVCAR-8 human ovarian carcinoma cells. Cancer Lett. 245:350–352. 2007. View Article : Google Scholar
21	Golden HB, Watson LE, Nizamutdinov D, Feng H, Gerilechaogetu F, Lal H, Verma SK, Mukhopadhyay S, Foster DM, Dillmann WH and Dostal DE: Anthrax lethal toxin induces acute diastolic dysfunction in rats through disruption of the phospholamban signaling network. Int J Cardiol. 168:3884–3895. 2013. View Article : Google Scholar : PubMed/NCBI
22	Kim AH, Khursigara G, Sun X, Franke TF and Chao MV: Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol. 21:893–901. 2001. View Article : Google Scholar : PubMed/NCBI