Glucosyltriazole amphiphile treatment attenuates breast cancer by modulating the AMPK signaling

• Published in: Drug development research Vol. 85; no. 4; pp. e22215 - n/a
• Main Authors: Chouhan, Neeraj Kumar, Eedara, Abhisheik, Talati, Mamta N., Ambadipudi, Sudha S. S. S. S., Andugulapati, Sai Balaji, Pabbaraja, Srihari
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.06.2024
• Subjects: AMP-activated protein kinase; AMP-Activated Protein Kinases - drug effects; AMP-Activated Protein Kinases - metabolism; AMPK; Animal models; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell culture; Cell cycle; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; click chemistry; Doxorubicin; Female; G1 phase; glucosyltriazole amphiphiles (GTAs); glycolipids; Humans; Hydroxyl groups; In vivo methods and tests; Kinases; MCF-7 Cells; Metastases; Mice; Mice, Inbred BALB C; Signal Transduction - drug effects; Triazoles - pharmacology; triple‐negative breast cancer (TNBC); Xenograft Model Antitumor Assays; AMPK; click chemistry; glycolipids; glucosyltriazole amphiphiles (GTAs); triple‐negative breast cancer (TNBC)
• ISSN: 0272-4391; 1098-2299; 1098-2299
• DOI: 10.1002/ddr.22215

Breast cancer is the second most frequent cancer among women. Out of various subtypes, triple‐negative breast cancers (TNBCs) account for 15% of breast cancers and exhibit more aggressive characteristics as well as a worse prognosis due to their proclivity for metastatic progression and limited therapeutic strategies. It has been demonstrated that AMP‐activated protein kinase (AMPK) has context‐specific protumorigenic implications in breast cancer cells. A set of glucosyltriazole amphiphiles, consisting of acetylated (9a‐h) and unmodified sugar hydroxyl groups (10a‐h), were synthesized and subjected to in vitro biological evaluation. Among them, 9h exhibited significant anticancer activity against MDA‐MB‐231, MCF‐7, and 4T1 cell lines with IC50 values of 12.5, 15, and 12.55 μM, respectively. Further, compound 9h was evaluated for apoptosis and cell cycle analysis in in vitro models (using breast cancer cells) and antitumour activity in an in vivo model (orthotopic mouse model using 4T1 cells). Annexin‐V assay results revealed that treatment with 9h caused 34% and 28% cell death at a concentration of 15 or 7.5 μM, respectively, while cell cycle analysis demonstrated that 9h arrested the cells at the G2/M or G1 phase in MCF‐7, MDA‐MB‐231 and 4T1 cells, respectively. Further, in vivo, investigation showed that compound 9h exhibited equipotent as doxorubicin at 7.5 mg/kg, and superior efficacy than doxorubicin at 15 mg/kg. The mechanistic approach revealed that 9h showed potent anticancer activity in an in vivo orthotopic model (4T1 cells) partly by suppressing the AMPK activation. Therefore, modulating the AMPK activation could be a probable approach for targeting breast cancer and mitigating cancer progression.