Rhein Augments Antiproliferative Effects of Atezolizumab Based on Breast Cancer (4T1) Regression

Abstract

Rhein, an anthraquinone extracted from rhubarb, is used in traditional Chinese medicine for diuresis, diarrhoea, inflammation, and immune regulation. Atezolizumab, a programmed cell death ligand 1 monoclonal antibody, is mainly used to treat bladder cancer and non-small cell lung cancer unresponsive to chemotherapy. We explored the effects of rhein and atezolizumab in combination on breast cancer. Mice with established 4T1 breast cancer xenografts were administered rhein (10 mg/kg) and atezolizumab (10 mg/kg), alone and in combination, and the effects on tumour growth were evaluated. The proportion of CD8+ T cells in the spleen and tumour tissue, the levels of TNF-α, and interleukin-6 in serum as well as the mRNA levels of apoptotic factors (caspase-3, caspase-8, caspase-9, and Bax/Bcl-2) were also evaluated. All of the treatment groups had inhibitory effects on the xenograft tumour growth, with results that were significantly different from those in the control group. In addition, the proportion of CD8+ T cells in the spleen and tumour was significantly increased in the combination therapy group and was significantly different from the other treatment groups. The serum levels of TNF-α and IL-6 were significantly increased in the rhein and combination therapy groups. Finally, the levels of various apoptotic factors in tumour tissues were significantly higher in the combination treatment group than those in the other groups. Administration of rhein, atezolizumab, or their combination all had therapeutic effects on 4T1 breast cancer xenografts in mice, with the combination treatment having stronger effects.

Key words

rhein - atezolizumab - combined therapy - 4T1 - apoptosis factors

• References

• 1 Peigen X, Liyi H, Liwei W. Ethnopharmacologic study of Chinese rhubarb. J Ethnopharmacol 1994; 10: 275-293
• 2 He ZH, Zhou R, He MF, Lau CB, Yue GG, Ge W, But PP. Anti-angiogenic effect and mechanism of rhein from Rhizoma Rhei . Phytomedicine 2011; 18: 470-478
• 3 Ma BL, Ma YM, Yan DM, Zhou H, Shi R, Wang TM, Yang Y, Wang CH, Zhang N. Effective constituents in Xiexin Decoction for anti-inflammation. J Ethnopharmacol 2009; 125: 151-156
• 4 Sun H, Luo G, Chen D, Xiang Z. A comprehensive and system review for the pharmacological mechanism of action of rhein, an active anthraquinone ingredient. Front Pharmacol 2016; 7: 247
• 5 Li WF, Dai H, Ou Q, Zuo GQ, Liu CA. Over expression of microRNA-3oa-5p inhibitits liver cancer cell proliferation and induces apoptosis by targeting MTDH/PTEN/AKT pathway. Tumour Biol 2016; 37: 5885-5895
• 6 Heo SK, Noh EK, Kim JY, Jegal S, Jeong Y, Cheon J, Koh S, Baek JH, Min YJ, Choi Y, Jo JC. Rhein augments ATRA-induced differentiation of acute promyelocytic leukemia cells. Phytomedicine 2018; 49: 66-74
• 7 Blacher E, Ben Baruch B, Levy A, Geva N, Green KD, Garneau-Tsodikova S, Fridman M, Stein R. Inhibition of glioma progression by a newly discovered CD38 inhibitor. Int J Cancer 2015; 136: 1422-1433
• 8 Schildberg FA, Klein SR, Freeman GJ, Sharpe AH. Coinhibitory pathway in the B7-CD28 ligand-receptor family. Immunity 2016; 44: 955-972
• 9 Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014; 515: 558-562
• 10 Park JO, Lee SI, Song SY, Kim K, Kim WS, Jung CW, Park YS, Im YH, Kang WK, Lee MH, Lee KS, Park K. Measuring response in solid tumors: comparison of RECIST and WHO response criteria. Jpn J Clin Oncol 2003; 33: 533-537
• 11 Maimela NR, Liu S, Zhang Y. Fates of CD8+T cells in tumor microenvironment. Comput Struct Biotechnol J 2018; 17: 1-13
• 12 Stennicke HR, Jürgensmeier JM, Shin H, Deveraux Q, Wolf BB, Yang X, Zhou Q, Ellerby HM, Ellerby LM, Bredesen D, Green DR, Reed JC, Froelich CJ, Salvesen GS. Pro-caspase-3 is a major physiologic target of caspase-8. J Biol Chem 1998; 273: 27084-27090
• 13 Wang D, Müller N, McPherson KG, Reichardt HM. Glucocorticoids engage different signal transduction pathways to induce apoptosis in thymocytes and mature T cells. J Immunol 2006; 176: 1695-1702
• 14 Roos WP, Kaina B. DNA damage-induced cell death by apoptosis. Trends Mol Med 2006; 12: 440-450
• 15 Sanghi DK, Tiwle R. Importance of village plant rhubarb: review. Int J Pharma Res Health Sci 2016; 4: 1438-1443
• 16 Cichewicz RH, Zhang Y, Seeram NP, Nair MG. Inhibition of human tumor cell proliferation by novel anthraquinones from daylilies. Life Sci 2004; 74: 1791-1799
• 17 Harary M, Reardon DA, Iorgulescu JB. Efficacy and safety of immune checkpoint blockade for brain metastases. CNS Oncol 2019; 8: CNS33
• 18 Iga N, Otsuka A, Yamamoto Y, Nakashima C, Honda T, Kitoh A, Nakajima S, Egawa G, Nomura T, Dainichi T, Matsushita S, Tanizaki H, Yamamoto Y, Funakoshi T, Fujisawa Y, Fujimura T, Hata H, Ishida Y, Kabashima K. Accumulation of exhausted CD8+ T cells in extramammary Pagetʼs disease. PLoS One 2019; 14: e0211135
• 19 Bergmann J, Müller M, Baumann N, Reichert M, Heneweer C, Bolik J, Lücke K, Gruber S, Carambia A, Boretius S, Leuschner I, Becker T, Rabe B, Herkel J, Wunderlich FT, Mittrücker HW, Rose-John S, Schmidt-Arras D. IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology 2017; 65: 89-103
• 20 Dolatkhah H, Movahedian A, Somi MH, Aghaei M, Samadi N, Mirza-Aghazade A, Esfahani A. Effect of PUFAs oral administration on the amount of apoptotic caspases enzymes in gastric cancer patients undergoing chemotherapy. Anticancer Agents Med Chem 2017; 17: 93-101
• 21 Heulot M, Chevalier N, Puyal J, Margue C, Michel S, Kreis S, Kulms D, Barras D, Nahimana A, Widmann C. The TAT-RasGAP317–326 anti-cancer peptide can kill in a caspase-, apoptosis-, and necroptosis-independent manner. Oncotarget 2016; 7: 64342-64359
• 22 Duan XX, Ou JS, Li Y, Su JJ, Ou C, Yang C, Yue HF, Ban KC. Dynamic expression of apoptosis-related genes during development of laboratory hepatocellular carcinoma and its relation to apoptosis. World J Gastroenterol 2005; 11: 4740-4744