Targeting the ataxia telangiectasia mutated pathway for effective therapy against hirsutine-resistant breast cancer cells

Abstract

Abstract. The present authors have recently demonstrated that hirsutine, one of the major alkaloids in Uncaria species, promotes cell apoptosis by inducing DNA damage and suppresses metastasis of breast cancer cells. Despite its potent anti-cancer activity, certain types of human breast cancer cells exhibit resistance to hirsutine. To maximize the clinical utility of hirsutine therapy against breast cancer, it is critical to explore the underlying mechanism that protects hirsutine-resistant breast cancer cell lines. To identify potential targets for overcoming hirsutine-resistance, the present study investigated a library of kinase inhibitors in combination with hirsutine treatment in the hirsutine-resistant human breast carcinoma MCF-7 cell line. Amongst the 96 compounds tested, inhibitors of the ataxia telangiectasia mutated (ATM) pathway sensitized MCF-7 cells to hirsutine-induced cell death along with a sustained DNA damage response. This sensitization of MCF-7 cells to the hirsutine-induced DNA damage response by interfering with the ATM pathway did not require p53. Instead, radical oxygen species generation was significantly increased in hirsute and ATM inhibitor-treated MCF-7 cells. In conclusion, the present findings suggest the importance of the ATM pathway for optimizing the anti-cancer effect of hirsutine in breast cancer cells.

Hirsutine, an Emerging Natural Product with Promising Therapeutic Benefits: A Systematic Review

“…A recent study found that HSN causes mitochondrial death by causing ATP depletion, the formation of ROS, the loss of mitochondrial membrane potential, and the discharge of cytochrome C (Cyt C) [ 34 ]. Additionally, to overcome HSN resistance, it may be helpful to disrupt the ataxia telangiectasia mutated (ATM) pathway, which results in ROS production and a p53-independent DNA damage response in breast cancer cells [ 21 ].…”

“…According to a study by Meng et al (2021), HCN showed cytotoxicity against Jurkat clone E6-1 tumor cells [ 25 ]. In a different study, it was discovered that HSN exhibits strong cytotoxicity against human breast cancer cell lines, including MCF-7, MDA-MB-231, MCF-10A, BT474, and MDA-MB-453 with concentrations ranging from 6.25−160 M ( Table 3 ) [ 20 , 21 , 22 , 23 , 24 ].…”

“…Published research showed that HSN exhibits a depressant effect on the central nervous system (CNS) in mice, a weak antispasmodic effect on the intestine of mice, and a lowering effect on blood pressure in rats [ 17 ]. Pharmacological studies have shown that HSN may have therapeutic benefits in treating certain conditions as it exerts anti-inflammatory (preeclampsia) [ 18 ], antiviral (dengue fever and dengue hemorrhagic fever) [ 19 ], anticancer activity (breast and lung cancers) [ 20 , 21 , 22 , 23 , 24 ], antitumor [ 25 ], anti-diabetic [ 26 ], antihypertensive, negative chronotropic, and antiarrhythmic activity [ 27 ]. It can also be used to treat and manage myocardial infarction, ischemia-reperfusion (I/R) trauma [ 28 ], brain inflammation [ 29 ], cerebral ischemia [ 30 ], cardiovascular diseases (cardiomyocytes) [ 31 ], anti-hypertension [ 14 , 32 ], hypotensive and vasodilatory effects [ 33 ], lung cancer [ 34 ], thrombolytic effects (thrombocytopenia) [ 35 ], and neurogenerative diseases and disorders such as neuronal death [ 36 ].…”

Association of ATM and BMI‐1 genetic variation with breast cancer risk in Han Chinese

“…In this study, we focused on 2 cancer‐predisposing genes, ATM and BMI‐1, in association with breast cancer. The involvement of ATM and BMI‐1 in carcinogenesis is biologically plausible . ATM is an acronym for ataxia telangiectasia mutated.…”

“…The involvement of ATM and BMI-1 in carcinogenesis is biologically plausible. [15][16][17][18] ATM is an acronym for ataxia telangiectasia mutated. ATM is a serine/threonine kinase involving in DNA damage repair, cell arrest and apoptosis, and chromatin remodelling.…”