Avermectin B1 Mediates Antitumor Activity and Induces Autophagy in Osteosarcoma Through the AMPK/ULK1 Signaling Pathway

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 2024 Sep 5

PMID 39235611

Authors

Xiang Fei

Zhaohui Li

Zhen Pan

Yonghui Liang

Chen Tan

Dongdong Cheng

QingCheng Yang

Affiliations

Soon will be listed here.

Abstract

Background: Osteosarcoma is the most common malignant bone tumor in children and adolescents. Conventional chemotherapy remains unsatisfactory due to drug toxicity and resistance issues. Therefore, there is an urgent need to develop more effective treatments for advanced osteosarcoma. In the current study, we focused on evaluating the anticancer efficacy of avermectin B1, a novel avermectin analog, against osteosarcoma cells.

Methods: The half-inhibitory concentration of avermectin B1 was calculated in three osteosarcoma cell lines. Then, functional experiments were conducted to evaluate the effects of avermectin B1 on cell proliferation, the cell cycle, apoptosis and autophagy. Moreover, the AMPK/ULK1 signaling pathway was detected by Western blot assay. Finally, the in vivo effect of avermectin B1 on tumor growth and metastasis was investigated using the xenograft mouse model. To examine the role of the AMPK/ULK1 pathway, an AMPK-specific inhibitor (dorsomorphin) was used in combination with avermectin B1.

Results: Avermectin B1 inhibited the proliferation of osteosarcoma cells in a dose-dependent manner based on CCK8 and colony formation assays. Then, it was found to inhibit migration and invasion by wound healing assay and cell migration and invasion assay. In addition, avermectin B1 induced osteosarcoma cell apoptosis and autophagy. In vivo, avermectin B1 effectively inhibited osteosarcoma cell growth and pulmonary metastasis. Mechanistically, avermectin B1 activated the AMPK/ULK1 pathway to exert antitumor activity in vitro and in vivo. Dorsomorphin significantly attenuated the Avermectin B1-induced antitumor activities.

Conclusion: Our study suggests that avermectin B1 is a potential agent to treat osteosarcoma cells through the AMPK/ULK1 signaling pathway.

References

Wang K, Gao W, Dou Q, Chen H, Li Q, Nice E . Ivermectin induces PAK1-mediated cytostatic autophagy in breast cancer. Autophagy. 2016; 12(12):2498-2499. PMC: 5173258. DOI: 10.1080/15548627.2016.1231494. View

Kwon Y, Petrie K, Leibovitch B, Zeng L, Mezei M, Howell L . Selective Inhibition of SIN3 Corepressor with Avermectins as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer. Mol Cancer Ther. 2015; 14(8):1824-36. PMC: 4529816. DOI: 10.1158/1535-7163.MCT-14-0980-T. View

Drinyaev V, Mosin V, Kruglyak E, Novik T, Sterlina T, Ermakova N . Antitumor effect of avermectins. Eur J Pharmacol. 2004; 501(1-3):19-23. DOI: 10.1016/j.ejphar.2004.08.009. View

Harrison D, Geller D, Gill J, Lewis V, Gorlick R . Current and future therapeutic approaches for osteosarcoma. Expert Rev Anticancer Ther. 2017; 18(1):39-50. DOI: 10.1080/14737140.2018.1413939. View

Cully D, Vassilatis D, Liu K, Paress P, Van der Ploeg L, Schaeffer J . Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature. 1994; 371(6499):707-11. DOI: 10.1038/371707a0. View

Roach P . AMPK -> ULK1 -> autophagy. Mol Cell Biol. 2011; 31(15):3082-4. PMC: 3147606. DOI: 10.1128/MCB.05565-11. View

Caly L, Druce J, Catton M, Jans D, Wagstaff K . The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020; 178:104787. PMC: 7129059. DOI: 10.1016/j.antiviral.2020.104787. View

Korystov Y, Ermakova N, Kublik L, Levitman M, Shaposhnikova V, Mosin V . Avermectins inhibit multidrug resistance of tumor cells. Eur J Pharmacol. 2004; 493(1-3):57-64. DOI: 10.1016/j.ejphar.2004.03.067. View

Campbell W, Fisher M, Stapley E, Jacob T . Ivermectin: a potent new antiparasitic agent. Science. 1983; 221(4613):823-8. DOI: 10.1126/science.6308762. View

10.

Jang J, Eom J, Jeung H, Cheong J, Lee J, Kim J . AMPK-ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells. Clin Cancer Res. 2016; 23(11):2781-2794. DOI: 10.1158/1078-0432.CCR-16-1903. View

11.

Debnath J, Gammoh N, Ryan K . Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023; 24(8):560-575. PMC: 9980873. DOI: 10.1038/s41580-023-00585-z. View

12.

Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z . AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013; 17(1):113-24. PMC: 3545102. DOI: 10.1016/j.cmet.2012.12.001. View

13.

Gupta P, Onder T, Jiang G, Tao K, Kuperwasser C, Weinberg R . Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009; 138(4):645-659. PMC: 4892125. DOI: 10.1016/j.cell.2009.06.034. View

14.

Tang M, Hu X, Wang Y, Yao X, Zhang W, Yu C . Ivermectin, a potential anticancer drug derived from an antiparasitic drug. Pharmacol Res. 2020; 163:105207. PMC: 7505114. DOI: 10.1016/j.phrs.2020.105207. View

15.

Zhu S, Zhou J, Zhou Z, Zhu Q . Abamectin induces apoptosis and autophagy by inhibiting reactive oxygen species-mediated PI3K/AKT signaling in MGC803 cells. J Biochem Mol Toxicol. 2019; 33(7):e22336. DOI: 10.1002/jbt.22336. View

16.

Grunewald T, Alonso M, Avnet S, Banito A, Burdach S, Cidre-Aranaz F . Sarcoma treatment in the era of molecular medicine. EMBO Mol Med. 2020; 12(11):e11131. PMC: 7645378. DOI: 10.15252/emmm.201911131. View

17.

Asatryan L, Yardley M, Khoja S, Trudell J, Hyunh N, Louie S . Avermectins differentially affect ethanol intake and receptor function: implications for developing new therapeutics for alcohol use disorders. Int J Neuropsychopharmacol. 2014; 17(6):907-16. PMC: 4209915. DOI: 10.1017/S1461145713001703. View

18.

Sadykova L, Ntekim A, Muyangwa-Semenova M, Rutland C, Jeyapalan J, Blatt N . Epidemiology and Risk Factors of Osteosarcoma. Cancer Invest. 2020; 38(5):259-269. DOI: 10.1080/07357907.2020.1768401. View

19.

Strauss S, Frezza A, Abecassis N, Bajpai J, Bauer S, Biagini R . Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32(12):1520-1536. DOI: 10.1016/j.annonc.2021.08.1995. View

20.

Kim J, Kundu M, Viollet B, Guan K . AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011; 13(2):132-41. PMC: 3987946. DOI: 10.1038/ncb2152. View