Gomisin A enhances the antitumor effect of paclitaxel by suppressing oxidative stress in ovarian cancer

Wang,Taiwei; Liu,Jian; Huang,Xuemiao; Zhang,Chuanqi; Shangguan,Mengyuan; Chen,Junyu; Wu,Shan; Chen,Mengmeng; Yang,Zhaoyun; Zhao,Shuhua

doi:10.3892/or.2022.8417

Gomisin A enhances the antitumor effect of paclitaxel by suppressing oxidative stress in ovarian cancer

Authors:
- Taiwei Wang
- Jian Liu
- Xuemiao Huang
- Chuanqi Zhang
- Mengyuan Shangguan
- Junyu Chen
- Shan Wu
- Mengmeng Chen
- Zhaoyun Yang
- Shuhua Zhao
View Affiliations

Affiliations: Department of Gynaecology and Obstetrics, The Second Hospital, Jilin University, Changchun, Jilin 130021, P.R. China, Department of Rehabilitation, School of Nursing, Jilin University, Changchun, Jilin 130022, P.R. China, Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
Published online on: September 27, 2022 https://doi.org/10.3892/or.2022.8417
Article Number: 202
Copyright: © Wang 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

Gomisin A (GA) is an effective component of Schisandra. The crude extracts of Schisandra chinensis and its active ingredients have been shown to inhibit multidrug resistance in tumour cells. Reactive oxygen species (ROS) have different roles in cancer and may contribute to therapy resistance. The human ovarian cancer (OC) cell lines SKOV3 and A2780, and a mouse model of OC, were used in the present study. MTT assay, colony formation assay, flow cytometry, western blot analysis, and haematoxylin and eosin (H&E) staining were performed to determine the antitumor effect of GA and paclitaxel (PTX) in vitro and in vivo. The ROS inhibitor N‑acetyl cysteine (NAC) was used to assess the mechanism underlying the chemosensitizing effects of GA. Notably, the proliferation of OC cells was inhibited by PTX, which could be enhanced by the ROS inhibitor NAC or GA. Treatment with NAC + PTX or GA + PTX enhanced the cell cycle arrest, but not apoptosis, induced by PTX. Moreover, the molecular mechanism underlying this effect may be that GA decreases the levels of ROS in ovarian cancer cells and inhibits cell cycle progression by downregulating the expression of the cell cycle proteins cyclin‑dependent kinase 4 and cyclin B1. In conclusion, the combination of PTX and the ROS inhibitor GA may be a novel strategy in OC chemotherapy.

View Figures

View References

1	Merritt MA, Rice MS, Barnard ME, Hankinson SE, Matulonis UA, Poole EM and Tworoger SS: Pre-diagnosis and post-diagnosis use of common analgesics and ovarian cancer prognosis (NHS/NHSII): A cohort study. Lancet Oncol. 19:1107–1116. 2018. View Article : Google Scholar : PubMed/NCBI
2	Liu J and Matulonis UA: New strategies in ovarian cancer: Translating the molecular complexity of ovarian cancer into treatment advances. Clin Cancer Res. 20:5150–5156. 2014. View Article : Google Scholar : PubMed/NCBI
3	du Bois A, Kristensen G, Ray-Coquard I, Reuss A, Pignata S, Colombo N, Denison U, Vergote I, Del Campo JM, Ottevanger P, et al: Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 17:78–89. 2016. View Article : Google Scholar : PubMed/NCBI
4	Majidi A, Na R, Dixon-Suen S, Jordan SJ and Webb PM: Common medications and survival in women with ovarian cancer: A systematic review and meta-analysis. Gynecol Oncol. 157:678–685. 2020. View Article : Google Scholar : PubMed/NCBI
5	van der Hel OL, Timmermans M, van Altena AM, Kruitwagen RFPM, Slangen BFM, Sonke GS, van de Vijver KK and van der Aa MA: Overview of non-epithelial ovarian tumours: Incidence and survival in the Netherlands, 1989–2015. Eur J Cancer. 118:97–104. 2019. View Article : Google Scholar : PubMed/NCBI
6	Zierhut C, Yamaguchi N, Paredes M, Luo JD, Carroll T and Funabiki H: The cytoplasmic DNA sensor cGAS promotes mitotic cell death. Cell. 178:302–315.e23. 2019. View Article : Google Scholar : PubMed/NCBI
7	Koshiyama M, Matsumura N, Imai S, Yamanoi K, Abiko K, Yoshioka Y, Yamaguchi K, Hamanishi J, Baba T and Konishi I: Combination of aprepitant, azasetron, and dexamethasone as antiemetic prophylaxis in women with gynecologic cancers receiving paclitaxel/carboplatin therapy. Med Sci Monit. 23:826–833. 2017. View Article : Google Scholar : PubMed/NCBI
8	Ren F, Shen J, Shi H, Hornicek FJ, Kan Q and Duan Z: Novel mechanisms and approaches to overcome multidrug resistance in the treatment of ovarian cancer. Biochim Biophys Acta. 1866:266–275. 2016.PubMed/NCBI
9	Li Z, He X, Liu F, Wang J and Feng J: A review of polysaccharides from Schisandra chinensis and Schisandra sphenanthera: Properties, functions and applications. Carbohydr Polym. 184:178–190. 2018. View Article : Google Scholar : PubMed/NCBI
10	Lv XJ, Zhao LJ, Hao YQ, Su ZZ, Li JY, Du YW and Zhang J: Schisandrin B inhibits the proliferation of human lung adenocarcinoma A549 cells by inducing cycle arrest and apoptosis. Int J Clin Exp Med. 8:6926–6936. 2015.PubMed/NCBI
11	Xu Y, Liu Z, Sun J, Pan Q, Sun F, Yan Z and Hu X: Schisandrin B prevents doxorubicin-induced chronic cardiotoxicity and enhances its anticancer activity in vivo. PLoS One. 6:e283352011. View Article : Google Scholar : PubMed/NCBI
12	Chen Y, Shi S, Wang H, Li N, Su J, Chou G and Wang S: A Homogeneous polysaccharide from fructus Schisandra chinensis (Turz.) baill induces mitochondrial apoptosis through the Hsp90/AKT signalling pathway in HepG2 cells. Int J Mol Sci. 17:10152016. View Article : Google Scholar : PubMed/NCBI
13	Chun JN, Cho M, So I and Jeon JH: The protective effects of Schisandra chinensis fruit extract and its lignans against cardiovascular disease: A review of the molecular mechanisms. Fitoterapia. 97:224–233. 2014. View Article : Google Scholar : PubMed/NCBI
14	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
15	Young Park J, Wook Yun J, Whan Choi Y, Ung Bae J, Won Seo K, Jin Lee S, Youn Park S, Whan Hong K and Kim CD: Antihypertensive effect of gomisin A from Schisandra chinensis on angiotensin II-induced hypertension via preservation of nitric oxide bioavailability. Hypertens Res. 35:928–934. 2012. View Article : Google Scholar : PubMed/NCBI
16	Qu HM, Liu SJ and Zhang CY: Antitumor and antiangiogenic activity of Schisandra chinensis polysaccharide in a renal cell carcinoma model. Int J Biol Macromol. 66:52–56. 2014. View Article : Google Scholar : PubMed/NCBI
17	Han YH, Mun JG, Jeon HD, Park J, Kee JY and Hong SH: Gomisin A ameliorates metastatic melanoma by inhibiting AMPK and ERK/JNK-mediated cell survival and metastatic phenotypes. Phytomedicine. 68:1531472020. View Article : Google Scholar : PubMed/NCBI
18	Kee JY, Han YH, Mun JG, Park SH, Jeon HD and Hong SH: Gomisin A suppresses colorectal lung metastasis by inducing AMPK/p38-mediated apoptosis and decreasing metastatic abilities of colorectal cancer cells. Front Pharmacol. 9:9862018. View Article : Google Scholar : PubMed/NCBI
19	Alexandre J, Hu Y, Lu W, Pelicano H and Huang P: Novel action of paclitaxel against cancer cells: Bystander effect mediated by reactive oxygen species. Cancer Res. 67:3512–3517. 2007. View Article : Google Scholar : PubMed/NCBI
20	de Sá Junior PL, Câmara DAD, Porcacchia AS, Fonseca PMM, Jorge SD, Araldi RP and Ferreira AK: The roles of ROS in cancer heterogeneity and therapy. Oxid Med Cell Longev. 2017:24679402017. View Article : Google Scholar : PubMed/NCBI
21	Harris IS and DeNicola GM: The complex interplay between antioxidants and ROS in cancer. Trends Cell Biol. 30:440–451. 2020. View Article : Google Scholar : PubMed/NCBI
22	Prasad S, Gupta SC and Tyagi AK: Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals. Cancer Lett. 387:95–105. 2017. View Article : Google Scholar : PubMed/NCBI
23	Chen J, Liu J, Wu S, Liu W, Xia Y, Zhao J, Yang Y, Wang Y, Peng Y and Zhao S: Atrazine promoted epithelial ovarian cancer cells proliferation and metastasis by inducing low dose reactive oxygen species (ROS). Iran J Biotechnol. 19:e26232021.PubMed/NCBI
24	Chen J, Xia Y, Peng Y, Wu S, Liu W, Zhang H, Wang T, Yang Z, Zhao S and Zhao L: Analysis of the association between KIN17 expression and the clinical features/prognosis of epithelial ovarian cancer, and the effects of KIN17 in SKOV3 cells. Oncol Lett. 21:4752021. View Article : Google Scholar : PubMed/NCBI
25	Zeng Z, Wang Q, Yang X, Ren Y, Jiao S, Zhu Q, Guo D, Xia K, Wang Y, Li C and Wang W: Qishen granule attenuates cardiac fibrosis by regulating TGF-β/Smad3 and GSK-3β pathway. Phytomedicine. 62:1529492019. View Article : Google Scholar : PubMed/NCBI
26	Takanche JS, Kim JE, Han SH and Yi HK: Effect of gomisin A on osteoblast differentiation in high glucose-mediated oxidative stress. Phytomedicine. 66:1531072020. View Article : Google Scholar : PubMed/NCBI
27	Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, et al: CDK4/6 inhibition triggers anti-tumour immunity. Nature. 548:471–475. 2017. View Article : Google Scholar : PubMed/NCBI
28	Jiang B, Ni H, Zhou Z and Li Y: Parkin enhances sensitivity of paclitaxel to NPC by arresting cell cycle. Pathol Res Pract. 216:1527552020. View Article : Google Scholar : PubMed/NCBI
29	Ahn JH, Lee HS, Lee JS, Lee YS, Park JL, Kim SY, Hwang JA, Kunkeaw N, Jung SY, Kim TJ, et al: nc886 is induced by TGF-β and suppresses the microRNA pathway in ovarian cancer. Nat Commun. 9:11662018. View Article : Google Scholar : PubMed/NCBI
30	Han YH, Kee JY and Hong SH: Gomisin A alleviates obesity by regulating the phenotypic switch between white and brown adipocytes. Am J Chin Med. 49:1929–1948. 2021. View Article : Google Scholar : PubMed/NCBI
31	Hao LJ, Lin RA, Chen LC, Wang JL, Chen IS, Kuo CC, Chou CT, Chien JM and Jan CR: Action of the natural compound gomisin a on Ca²⁺ movement in human prostate cancer cells. Chin J Physiol. 65:151–157. 2022. View Article : Google Scholar : PubMed/NCBI
32	da Cunha Santos G, Shepherd FA and Tsao MS: EGFR mutations and lung cancer. Annu Rev Pathol. 6:49–69. 2011. View Article : Google Scholar : PubMed/NCBI
33	Talukdar S, Emdad L, Das SK and Fisher PB: EGFR: An essential receptor tyrosine kinase-regulator of cancer stem cells. Adv Cancer Res. 147:161–188. 2020. View Article : Google Scholar : PubMed/NCBI
34	Ko YH, Jeong M, Jang DS and Choi JH: Gomisin L1, a lignan isolated from Schisandra berries, induces apoptosis by regulating NADPH oxidase in human ovarian cancer cells. Life (Basel). 11:8582021.PubMed/NCBI
35	Kretzmann NA, Chiela E, Matte U, Marroni N and Marroni CA: N-acetylcysteine improves antitumoural response of Interferon alpha by NF-kB downregulation in liver cancer cells. Comp Hepatol. 11:42012. View Article : Google Scholar : PubMed/NCBI
36	Liu B, Huang X, Li Y, Liao W, Li M, Liu Y, He R, Feng D, Zhu R and Kurihara H: JS-K, a nitric oxide donor, induces autophagy as a complementary mechanism inhibiting ovarian cancer. BMC Cancer. 19:6452019. View Article : Google Scholar : PubMed/NCBI
37	Mendes S, Sá R, Magalhães M, Marques F, Sousa M and Silva E: The role of ROS as a double-edged sword in (In)Fertility: The impact of cancer treatment. Cancers (Basel). 14:15852022. View Article : Google Scholar : PubMed/NCBI
38	Okon IS and Zou MH: Mitochondrial ROS and cancer drug resistance: Implications for therapy. Pharmacol Res. 100:170–174. 2015. View Article : Google Scholar : PubMed/NCBI
39	Ma N, Liu P, He N, Gu N, Wu FG and Chen Z: Action of gold nanospikes-based nanoradiosensitizers: Cellular internalization, radiotherapy, and autophagy. ACS Appl Mater Interfaces. 9:31526–31542. 2017. View Article : Google Scholar : PubMed/NCBI
40	Zhao F, Gao Y, Chu X, Chen J, Huang L, Zhao J, Zhang J and Zhao S: ROS attenuates the antitumor effect of Raddeanin on ovarian cancer cells Skov3. Int J Clin Exp Pathol. 10:8292–8302. 2017.PubMed/NCBI
41	Wong RS: Apoptosis in cancer: From pathogenesis to treatment. J Exp Clin Cancer Res. 30:872011. View Article : Google Scholar : PubMed/NCBI
42	Jiang S, Zhang E, Ruan H, Ma J, Zhao X, Zhu Y, Xie X, Han N, Li J, Zhang H, et al: Actinomycin V induces apoptosis associated with mitochondrial and PI3K/AKT pathways in human CRC cells. Mar Drugs. 19:5992021. View Article : Google Scholar : PubMed/NCBI
43	Wang TH, Wang HS and Soong YK: Paclitaxel-induced cell death: Where the cell cycle and apoptosis come together. Cancer. 88:2619–2628. 2000. View Article : Google Scholar : PubMed/NCBI
44	Zhang CC, Li CG, Wang YF, Xu LH, He XH, Zeng QZ, Zeng CY, Mai FY, Hu B and Ouyang DY: Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation. Apoptosis. 24:312–325. 2019. View Article : Google Scholar : PubMed/NCBI
45	Manfredi JJ and Horwitz SB: Taxol: An antimitotic agent with a new mechanism of action. Pharmacol Ther. 25:83–125. 1984. View Article : Google Scholar : PubMed/NCBI
46	Zhuang Y, Wu H, Wang X, He J, He S and Yin Y: Resveratrol attenuates oxidative stress-induced intestinal barrier injury through PI3K/Akt-mediated Nrf2 signaling pathway. Oxid Med Cell Longev. 2019:75918402019. View Article : Google Scholar : PubMed/NCBI
47	Hao Y, Li Y, Liu J, Wang Z, Gao B, Zhang Y and Wang J: Protective effect of Chrysanthemum morifolium cv. Fubaiju hot-water extracts against ARPE-19 cell oxidative damage by activating PI3K/Akt-mediated Nrf2/HO-1 signaling pathway. Front Nutr. 8:6489732021. View Article : Google Scholar : PubMed/NCBI
48	Ren Y, Geng R, Lu Q, Tan X, Rao R, Zhou H, Yang X and Liu W: Involvement of TGF-β and ROS in G1 cell cycle arrest induced by titanium dioxide nanoparticles under UVA irradiation in a 3D spheroid model. Int J Nanomedicine. 15:1997–2010. 2020. View Article : Google Scholar : PubMed/NCBI