Drugs modulating apoptosis: current status
Keywords:Apoptosis, Cell death, TRAIL, Bcl2, MDM2
Apoptosis (programmed cell death) is a natural process that helps in removing potentially harmful cells from the body and replacing it with normal ones. Like any other process, it is also subjected to lots of deregulations and can lead to diseases like cancer, neurodegenerative conditions, multiple sclerosis, Parkinson’s disease, autoimmune disorders and inappropriate death of cells after liver failure, stroke and myocardial infarction. The knowledge of the molecular mechanisms involved in apoptosis has been progressed tremendously. Thus, therapeutics targeting apoptosis have been emerged as a novel approach for treating various disease conditions. Current approaches induce or inhibit apoptosis by targeting the key regulators of apoptosis such as Bcl2 family of proteins, TRAIL, caspases, MDM2, IAPs and p53. While many apoptotic drugs proved its efficacy in preclinical studies, some are already approved and entered the clinical setting. Numerous novel approaches such as antisense therapy, gene therapy, recombinant biologics and combinatorial chemistry are being employed to target these regulators. This review focused on the pathways of apoptosis, various therapeutic targets in apoptosis and the drugs modulating these targets.
Cotran RS. Cellular pathology I: cell injury and cell death. In: Kumar V, Collins T, eds. Pathologic basis of disease. 8th ed. Philadelphia: Elsevier Saunders; 2005.
Gomez-Sintes R, Hernandez F, Lucas JJ, Avila J. GSK-3 mouse models to study neuronal apoptosis and neurodegeneration. Front Mol Neurosci. 2011;4:45-7.
Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516.
Solary E, Droin N, Sordet O, Rebe C, Filomenko R, Wotawa A, et al. Cell death pathways as targets for anticancer drugs. In: Sordet O, Rebe C, Filomenko R, eds. Anticancer development. 5th ed. San Diego: Academic Press; 2002.
Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin. 2005;55(3):178-94.
Wong RSY. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Rev. 2011;30:87-9.
Palacios C, Yerbes R, Sanchez T, Martin R, Cano A, Lopez-Rivas A. The long and winding road to cancer treatment: the TRAIL system. Curr Pharm Des. 2014;20(17):2819-33.
Rosa AJ, Gomez MA, Morales S, Padillo FJ, Muntane J. CD95 signaling in cancer treatment. Curr Pharm Des. 2014;20(17):2809-18.
Fischer U. New approaches and therapeutics targeting apoptosis in disease. Pharmacol Rev. 2005;57(2):187-215.
Kim R, Emi M, Tanabe K. Caspase-dependent and independent cell death pathways after DNA damage. Oncol Rep. 2005;14:595-9.
McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2013;5:18-20.
Fulda S, Vucic D. Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov. 2012;11(2):109-24.
Um H. Bcl-2 family proteins as regulators of cancer cell invasion and metastasis: a review focusing on mitochondrial respiration and reactive oxygen species. Oncotarget. 2016;7(5):5193-203.
Zhao Y, Aguilar A, Bernard D, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 inhibitors) in clinical trials for cancer treatment. J Med Chem. 2015;58(3):1038-52.
Kang MH, Oh SC, Lee HJ, Kang HN, Kim JL, Kim JS, et al. Metastatic function of BMP-2 in gastric cancer cells: the role of PI3K/AKT, MAPK, the NF-κB pathway, and MMP-9 expression. Exp Cell Res. 2011;317(12):1746-62.
Kisselev AF, Linden WAVD, Overkleeft HS. Proteasome inhibitors: an expanding army attacking a unique target. Chem Biol. 2012;19(1):99-115.
Accardi F, Toscani D, Bolzoni M, Palma BD, Aversa F, Giuliani N. Mechanism of action of bortezomib and the new proteasome inhibitors on myeloma cells and the bone microenvironment: impact on myeloma-induced alterations of bone remodeling. Biomed Res Int. 2015;15:172-88.