ABSTRACT
Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATP-competitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective. Notably, capivasertib (AZD5363), a potent ATP-competitive Akt inhibitor, received FDA approval in November 2023 for use in combination with the estrogen receptor degrader fulvestrant to treat breast cancer. Challenges remain, including improving selectivity, identifying biomarkers to tailor treatments, and enhancing therapeutic efficacy while minimizing adverse effects. Particularly covalent-allosteric inhibitors hold promise for future more effective and personalized treatments.
Subject(s)
Protein Kinase Inhibitors , Proto-Oncogene Proteins c-akt , Pyrimidines , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/therapeutic use , Allosteric Regulation/drug effects , Drug Approval , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Pyrroles/chemistry , Pyrroles/pharmacology , Pyrroles/chemical synthesis , AnimalsABSTRACT
At present, the growing spread of tumor cases worldwide renders the research of new promising and selective anticancer drugs urgent. The biological action of extracts of medicinal plants or their essential oils (EOs) is an emerging field of interest, since they could comprise a rich source of phytochemicals that can prove promising. In the present study, the biological activity and mechanism of action of the EO of Foeniculum vulgare subsp. piperitum fruits (FVPEO) were investigated using MTT assays, morphological analyses and western blotting in MDAMB231 cells, a triplenegative breast cancer cell line. The findings revealed that FVPEO could exert strong anticancer effects, causing a dosedependent inhibition of breast cancer MDAMB231 cell growth, accompanied with DNA condensation and fragmentation. The cytotoxic effect of FVPEO was counteracted by the addition of the antioxidant Nacetylcysteine and was associated with a marked increase in reactive oxygen species and stressrelated proteins; such as manganese superoxide dismutase, cJun, phosphocJun Nterminal kinase and nuclear factor E2related factor 2, and the latter's transcriptional targets, Heme oxygenase1 and NAD(P)H quinone oxidoreductase 1 (NQO1). As evidenced by the activation of caspase3 and fragmentation of poly(ADPribose) polymerase1, which are typical apoptosis markers, FVPEO promoted apoptotic cell death accompanied with an increase in phosphorylated H2A histone family member X and the activation of the NQO1/p53 axis. In combination, the present experiments provided evidence that FVPEO could represent a reservoir of biologically active compounds suitable for both cancer prevention and treatment.
