Anticancer potential of novel α,β-unsaturated γ-lactam derivatives targeting the PI3K/AKT signaling pathway

被引:12
作者
Brindisi, Matteo [1 ]
Frattaruolo, Luca [1 ]
Mancuso, Raffaella [2 ]
Piccionello, Antonio Palumbo [3 ]
Ziccarelli, Ida [2 ]
Catto, Marco [4 ]
Nicolotti, Orazio [4 ]
Altomare, Cosimo D. [4 ]
Gabriele, Bartolo [2 ]
Cappello, Anna Rita [1 ]
机构
[1] Univ Calabria, Dept Pharm Hlth & Nutr Sci, Via P Bucci, I-87036 Arcavacata Di Rende, CS, Italy
[2] Univ Calabria, Dept Chem & Chem Technol, Lab Ind & Synthet Organ Chem LISOC, Via Pietro Bucci 12-C, I-87036 Arcavacata Di Rende, CS, Italy
[3] Univ Palermo, Dept Biol Chem & Pharmaceut Sci & Technol STEBICE, Viale Sci Ed17, I-90128 Palermo, Italy
[4] Univ Bari Aldo Moro, Dept Pharm Pharmaceut Sci, Via E Orabona 4, I-70126 Bari, Italy
关键词
alpha; beta-Unsaturated lactams; alpha-Methylene-gamma-lactams; Breast cancer; Cytotoxicity; Apoptosis; PI3K/AKT signaling pathway; PI3K/MTOR INHIBITORS; PI3K-AKT PATHWAY; CANCER; ALPHA; GSK2126458; NVP-BEZ235; DISCOVERY; NVP-BYL719; METASTASES; MUTATIONS;
D O I
10.1016/j.bcp.2021.114659
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Six recently synthesized alkyl (Z)-2-(2-oxopyrrolidin-3-ylidene)acetates were evaluated for their potential as cytotoxic and anticancer agents. All compounds were tested in the ER alpha positive MCF-7, triple negative MDA-MB-231, and Her2(+) SKBR-3 breast cancer cell lines. The most lipophilic derivatives, bearing the 4-isopropylphenyl (2) or 4-tert-butylphenyl (3) group at the gamma-lactam nitrogen, proved to be cytotoxic against all the cancer cell lines tested (IC50 values ranging from 18 to 63 mu M), exerting their greatest activity in SKBR-3 cells, with IC50 values of 33 and 18 mu M, respectively. Biological studies showed that the cytotoxic effects of 2 and 3 are accompanied by apoptotic death in breast cancer cells, and both compounds showed no significant toxicity on healthy cells (e.g., MCF-10A) and red blood cells. An in-depth mechanistic study based on molecular biology, immunoblotting analysis and in silico docking calculations suggested that alpha,beta-unsaturated gamma-lactam derivatives could interfere with the functioning of PI3K and PDK-1, two key enzymes in the PI3K/AKT signaling pathway, whose overactivation is related to the regulation of cell growth and survival in several malignancies.
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页数:15
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