Apoptosis is a process of programmed cell death, that is involved in keeping selective serotonin reuptake inhibitor by maintaining cell populations in tissues. Physiologically, apoptosis is essential for embryonic development, cell turnover, proper development of the immune system and hormone-dependent atrophy . It takes place through sequence of steps: disruption of cellular membranes, breakdown of cytoplasmic and nuclear skeleton, degradation of chromosomes, extrusion of cytosol and nuclear fragmentation . Balance between cell proliferation and apoptosis is critical for normal development of organisms and it is kept under tight control of group of pro and antiapoptotic proteins . Loss of this balance is a main characteristic of wide variety of diseases; excess apoptosis leads to Alzheimer\’s and Parkinson\’s diseases, AIDS and cardiovascular diseases, while loss of balance in favor of proliferation is common feature of various types of cancers [3,4]. Thus, apoptotic machinery pathways and the involved proteins have evaded as targets for rational therapeutic approaches against several diseases.
IAPs are attractive targets for anticancer therapy, as their inhibition, mainly XIAP, promotes apoptosis of cancerous cell and increase its sensitivity to chemotherapeutic agents. In this review, different types of Smac mimetics that antagonize the action of IAP were discussed. Several peptidomimetics and small molecule Smac mimetics were synthesized and biologically evaluated, where the poor pharmacokinetic properties were the main barrier to their clinical application. Several types of Smac mimetics were developed that belonged to monovalent (that target BIR3 on IAP) or bivalent (that concurrently target BIR2 and BIR3 regions) IAP inhibitors. Currently, several Smac mietics are in clinical trials including GDC-0152 2, GDC-0917 3, SM-406 7 and birinapant 12. Ongoing efforts are being exerted to further explore this field of targeted anticancer therapy.
Cancer is a major concern nowadays for research, although a range of therapies based on chemotherapy are available, but they are of limited efficacy or of serious adverse effects and associated with high levels of toxicity. Hence, many research are being performed for the aim to develop new chemotherapies with minimal side effects on mammalian cells. That was reachable through natural product compounds which were found to be a good source for both novel and potent bioactive compounds with minimal side effects in vivo [1–10].
Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadien-3,5-dione] Fig. 1, is a turmeric powder, extracted from the rhizome of the plant curcuma longa. Curcumin was found to be a highly pleiotropic molecule that interacts with a diverse range of molecular targets and hence it possess anti-proliferative activities against tumor cells in vitro, anti-inflammatory, antibacterial, antiviral and anti-hepatotoxic activities [11–14]. Since cancer is a result of the dys-regulation of multiple cell signaling pathways so curcumin\’s multi-targeting ability may be the key to its therapeutic potential against cancer. On the other hand, recent research revealed that chalcones possess cytotoxic activity, where tubulin inhibition and interference with microtubule formation were believed to be the main reason for this cytotoxicity; tubulin protein and microtubule formation are essential in cellular processes such as mitosis and cell replication and hence, the great similarity in structure between curcumin analogs and chalcones inspired their testing against tubulin activity .
Results and discussion
I would like to express my sincere thanks for the Future University in Egypt for funding my MSC study at Ain Shams University –Cairo- Egypt, also, Professor J.Gullbo; Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden for the great collaboration in this study.