Polysaccharides from <em>Annona muricata</em> leaves protect against cisplatin‑induced cytotoxicity in macrophages by alleviating mitochondrial dysfunction

Han,Jeong Moo; Song,Ha-Yeon; Kim,Kwang-Il; Park,Woo Yong; Park,Sang-Hyun; Byun,Eui-Baek; Byun,Eui-Hong

doi:10.3892/mmr.2022.12903

Polysaccharides from Annona muricata leaves protect against cisplatin‑induced cytotoxicity in macrophages by alleviating mitochondrial dysfunction

Authors:
- Jeong Moo Han
- Ha-Yeon Song
- Kwang-Il Kim
- Woo Yong Park
- Sang-Hyun Park
- Eui-Baek Byun
- Eui-Hong Byun
View Affiliations

Affiliations: Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Jeollabuk‑do 56212, Republic of Korea, Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea, Department of Food Science and Technology, Kongju National University, Yesan‑eup, Chungcheongnam‑do 340‑800, Republic of Korea
Published online on: November 30, 2022 https://doi.org/10.3892/mmr.2022.12903
Article Number: 16
Copyright: © Han 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

Cisplatin is a prominent chemotherapeutic agent that can induce significant damage to normal cells. Therefore, it is important to develop agents that protect normal cells without influencing the chemotherapeutic effect of cisplatin. The present study was conducted to explore the protective effects of Annona muricata leaf polysaccharides (ALPS) against cisplatin‑induced toxicity in macrophages. Apoptosis was assessed in macrophages and lung cancer cells to investigate the cytoprotective effect of ALPS, their effect on the production of cisplatin‑induced reactive oxygen species (ROS) and the loss of the mitochondrial transmembrane potential (MTP). Cisplatin, when used alone or in combination with ALPS, showed significant toxicity against A549 and H460 lung cancer cells. However, cisplatin‑induced cytotoxicity was suppressed by cotreatment of RAW 264.7 macrophages with ALPS. ALPS significantly inhibited the upregulation of Bax, cytosolic cytochrome c and caspases‑3, ‑8 and ‑9. Moreover, ALPS resulted in the cleavage of PARP and downregulation of Bcl‑2 levels in a concentration‑dependent manner, which ultimately led to a reduction in the apoptotic and necrotic populations of cisplatin‑treated RAW 264.7 macrophages. The suppression of the apoptotic signaling pathways was mediated through the reduction of ROS and MTP loss in cisplatin‑treated RAW 264.7 macrophages. In addition, ALPS alleviated cell damage by suppressing the mitochondrial apoptotic pathways in cisplatin‑treated bone marrow‑derived macrophages. Together, these findings suggested that ALPS may alleviate the toxic side effects of chemotherapeutic agents and act as a potential candidate for use as an effective adjuvant therapy.

View Figures

View References

1	Akazawa H: Cardiotoxicity of cancer chemotherapy-mechanisms and therapeutic approach. Gan To Kagaku Ryoho. 44:2058–2063. 2017.(In Japanese). PubMed/NCBI
2	Vineis P and Wild CP: Global cancer patterns: Causes and prevention. Lancet. 383:549–557. 2014. View Article : Google Scholar : PubMed/NCBI
3	Aiba K: Chemotherapy. Gan To Kagaku Ryoho. 31:706–711. 2004.(In Japanese). PubMed/NCBI
4	Rivankar S: An overview of doxorubicin formulations in cancer therapy. J Cancer Res Ther. 10:853–858. 2014. View Article : Google Scholar : PubMed/NCBI
5	Knezevic CE and Clarke W: Cancer chemotherapy: The case for therapeutic drug monitoring. Ther Drug Monit. 42:6–19. 2020. View Article : Google Scholar : PubMed/NCBI
6	Hong BY, Sobue T, Choquette L, Dupuy AK, Thompson A, Burleson JA, Salner AL, Schauer PK, Joshi P, Fox E, et al: Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis. Microbiome. 7:662019. View Article : Google Scholar : PubMed/NCBI
7	Chen RL, Wang Z, Huang P, Sun CH, Yu WY, Zhang HH, Yu CH and He JQ: Isovitexin potentiated the antitumor activity of cisplatin by inhibiting the glucose metabolism of lung cancer cells and reduced cisplatin-induced immunotoxicity in mice. Int Immunopharmacol. 94:1073572021. View Article : Google Scholar : PubMed/NCBI
8	Zhu H, Luo H, Zhang W, Shen Z, Hu X and Zhu X: Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Des Devel Ther. 10:1885–1895. 2016. View Article : Google Scholar : PubMed/NCBI
9	Ma Z, Xu L, Liu D, Zhang X, Di S, Li W, Zhang J, Reiter RJ, Han J, Li X and Yan X: Utilizing melatonin to alleviate side effects of chemotherapy: A potentially good partner for treating cancer with ageing. Oxid Med Cell Longev. 2020:68415812020. View Article : Google Scholar : PubMed/NCBI
10	Pearce A, Haas M, Viney R, Pearson SA, Haywood P, Brown C and Ward R: Incidence and severity of self-reported chemotherapy side effects in routine care: A prospective cohort study. PLoS One. 12:e01843602017. View Article : Google Scholar : PubMed/NCBI
11	Palipoch S, Punsawad C, Koomhin P and Suwannalert P: Hepatoprotective effect of curcumin and alpha-tocopherol against cisplatin-induced oxidative stress. BMC Complement Altern Med. 14:1112014. View Article : Google Scholar : PubMed/NCBI
12	Liu Z, Huang P, Law S, Tian H, Leung W and Xu C: Preventive effect of curcumin against chemotherapy-induced side-effects. Front Pharmacol. 9:13742018. View Article : Google Scholar : PubMed/NCBI
13	Feng T, Yang X, Kong Q and Lu J: Editorial: Food bioactive polysaccharides and their health functions. Front Nutr. 8:7462552021. View Article : Google Scholar : PubMed/NCBI
14	Yu Q, Nie SP, Wang JQ, Liu XZ, Yin PF, Huang DF, Li WJ, Gong DM and Xie MY: Chemoprotective effects of Ganoderma atrum polysaccharide in cyclophosphamide-induced mice. Int J Biol Macromol. 64:395–401. 2014. View Article : Google Scholar : PubMed/NCBI
15	Bao WR, Li ZP, Zhang QW, Li LF, Liu HB, Ma DL, Leung CH, Lu AP, Bian ZX and Han QB: Astragalus polysaccharide RAP selectively attenuates paclitaxel-induced cytotoxicity toward RAW 264.7 cells by reversing cell cycle arrest and apoptosis. Front Pharmacol. 9:15802018. View Article : Google Scholar : PubMed/NCBI
16	Byun EB, Song HY, Kim WS, Han JM, Seo HS, Park SH, Kim K and Byun EH: Protective effect of polysaccharides extracted from Cudrania tricuspidata fruit against cisplatin-induced cytotoxicity in macrophages and a mouse model. Int J Mol Sci. 22:75122021. View Article : Google Scholar : PubMed/NCBI
17	Paul J, Gnanam R, Jayadeepa RM and Arul L: Anti cancer activity on graviola, an exciting medicinal plant extract vs various cancer cell lines and a detailed computational study on its potent anti-cancerous leads. Curr Top Med Chem. 13:1666–1673. 2013. View Article : Google Scholar : PubMed/NCBI
18	Hajdu Z and Hohmann J: An ethnopharmacological survey of the traditional medicine utilized in the community of Porvenir, Bajo Paraguá Indian Reservation, Bolivia. J Ethnopharmacol. 139:838–857. 2012. View Article : Google Scholar : PubMed/NCBI
19	Oliveira AP, Sá I, Pereira DM, Gonçalves RF, Andrade PB and Valentão P: Exploratory studies on the in vitro anti-inflammatory potential of two herbal teas (Annona muricata L. and Jasminum grandiflorum L.), and relation with their phenolic composition. Chem Biodivers. 14:e17000022017. View Article : Google Scholar
20	Kim WS, Kim YE, Cho EJ, Byun EB, Park WY, Song HY, Kim K, Park SH and Byun EH: Neuroprotective effect of Annona muricata-derived polysaccharides in neuronal HT22 cell damage induced by hydrogen peroxide. Biosci Biotechnol Biochem. 84:1001–1012. 2020. View Article : Google Scholar : PubMed/NCBI
21	Byun EB, Song HY and Kim WS: Polysaccharides from Annona muricata leaves protect normal human epidermal keratinocytes and mice skin from radiation-induced injuries. Radiat Phys Chem. 170:1086722020. View Article : Google Scholar
22	Kim WS, Han JM, Song HY, Byun EH, Lim ST and Byun EB: Annona muricata L.-derived polysaccharides as a potential adjuvant to a dendritic cell-based vaccine in a thymoma-bearing model. Nutrients. 12:16022020. View Article : Google Scholar : PubMed/NCBI
23	Zhang X, Goncalves R and Mosser DM: The isolation and characterization of murine macrophages. Curr Protoc Immunol. Chapter 14: Unit 14.1. 2008. View Article : Google Scholar
24	Eruslanov E and Kusmartsev S: Identification of ROS using oxidized DCFDA and flow-cytometry. Methods Mol Biol. 594:57–72. 2010. View Article : Google Scholar : PubMed/NCBI
25	Makovec T: Cisplatin and beyond: Molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiol Oncol. 53:148–158. 2019. View Article : Google Scholar : PubMed/NCBI
26	Marullo R, Werner E, Degtyareva N, Moore B, Altavilla G, Ramalingam SS and Doetsch PW: Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS One. 8:e811622013. View Article : Google Scholar : PubMed/NCBI
27	Yang Y, Liu H, Liu F and Dong Z: Mitochondrial dysregulation and protection in cisplatin nephrotoxicity. Arch Toxicol. 88:1249–1256. 2014. View Article : Google Scholar : PubMed/NCBI
28	Hassan I, Chibber S and Naseem I: Ameliorative effect of riboflavin on the cisplatin induced nephrotoxicity and hepatotoxicity under photoillumination. Food Chem Toxicol. 48:2052–2058. 2010. View Article : Google Scholar : PubMed/NCBI
29	Khalaf AA, Hussein S, Tohamy AF, Marouf S, Yassa HD, Zaki AR and Bishayee A: Protective effect of Echinacea purpurea (Immulant) against cisplatin-induced immunotoxicity in rats. Daru. 27:233–241. 2019. View Article : Google Scholar : PubMed/NCBI
30	Hussain Y, Islam L, Khan H, Filosa R, Aschner M and Javed S: Curcumin-cisplatin chemotherapy: A novel strategy in promoting chemotherapy efficacy and reducing side effects. Phytother Res. 35:6514–6529. 2021. View Article : Google Scholar : PubMed/NCBI
31	Kumar S and Tchounwou PB: Molecular mechanisms of cisplatin cytotoxicity in acute promyelocytic leukemia cells. Oncotarget. 6:40734–40746. 2015. View Article : Google Scholar : PubMed/NCBI
32	Dasari S and Tchounwou PB: Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 740:364–378. 2014. View Article : Google Scholar : PubMed/NCBI
33	Yu S, Gong LS, Li NF, Pan YF and Zhang L: Galangin (GG) combined with cisplatin (DDP) to suppress human lung cancer by inhibition of STAT3-regulated NF-κB and Bcl-2/Bax signaling pathways. Biomed Pharmacother. 97:213–224. 2018. View Article : Google Scholar : PubMed/NCBI
34	Zhao X, Xiang H, Bai X, Fei N, Huang Y, Song X, Zhang H, Zhang L and Tong D: Porcine parvovirus infection activates mitochondria-mediated apoptotic signaling pathway by inducing ROS accumulation. Virol J. 13:262016. View Article : Google Scholar : PubMed/NCBI
35	Oyinloye BE, Adenowo AF and Kappo AP: Reactive oxygen species, apoptosis, antimicrobial peptides and human inflammatory diseases. Pharmaceuticals (Basel). 8:151–175. 2015. View Article : Google Scholar : PubMed/NCBI
36	Kleih M, Böpple K, Dong M, Gaißler A, Heine S, Olayioye MA, Aulitzky WE and Essmann F: Direct impact of cisplatin on mitochondria induces ROS production that dictates cell fate of ovarian cancer cells. Cell Death Dis. 10:8512019. View Article : Google Scholar : PubMed/NCBI