Another topic for research will
Another topic for research will be the combination of other cytotoxic agents with Aurora kinase inhibitors. Particularly interesting might be the combination of Aurora kinase inhibitors and agents that depend on the spindle checkpoint for their activity, such as the taxanes, given the importance of Aurora-B in regulating the spindle checkpoint. Pre-clinical data suggested synergy between several Aurora kinase inhibitors and daunorubicin, SN-38, vinorelbine, gemcitabine, docetaxel, oxaliplatin of 5-fluorouracil , .
Conflict of interest statement
Introduction The colorectal cancer (CRC) is the second leading cause of cancer related death in the developed countries, diagnosed as 146,940 patients per year and the incidence rate of CRC got higher in industrialized and western countries , . Particularly, the colon cancer has been ridden by sub-population of self-renewing cells termed as cancer stem cells (CSC), which can be regulated by abnormal DHAP events . Broadly, the cell cycle is the cyclic event to initiate division of growing cell into two exact daughter cells . The DNA replication occurs during the S (synthesis) phase, which is happening after DNA preparatory phase referred as G1 phase or first gap phase. After, a mitotic preparatory phase or G2 phase nuclear division starts to occur during M phase . The checkpoint between G1/S and G2/M phase has been regulated by active protein enlisted as cyclin dependent kinases (cdks), checkpoint kinases (chks), polo-like kinase, Aurora kinases, NIMA-related kinase (Neks), p53, BRCA1, SIRT1 and cyclin B1 . When compared to all other protein kinase family involved in cell cycle, the potent mitotic kinase, Aurora kinases play an important role in the regulation of mitosis . These are the key proteins to regulate chromosome duplication, mitotic spindle formation, mitotic checkpoint activation and cytokinesis , . Notably, the abnormal expression of Aurora kinases and SIRT1 shows disruption of the checkpoint at mitosis and spindle formation. These disruptions lead to genetic instability, aneuploidy, chromosome missegregation, monopolar and abnormal nuclei that trigger the tumor formation, which are known to be a hallmark for cancer progression . Hence, the Aurora kinases are thought as a potential marker for cancer progression. SIRT1 (Sirtuin 1) is a NAD+ depended class III histone deacetylase (HDAC) that mediate acetylation and deacetylation of both histone and non-histone proteins, which are playing an important role in mitosis progression . Especially class III HDAC of SIRT1 plays a pivotal role in epigenetic modification of chromatin structure, seen higher in various cancers such as colorectal cancer and breast cancer . Before SIRT1, the SIRT2 gene was first found in Saccharomyces cerevisiae that acts as a transcriptional silencer in telomerase . The SIRT2 has close homologs with family members of demalonylase or desuccinylase and mono-ADP ribosyl transferase to NAD+ dependent deacetylase , . This SIRT1 has involved in many biological processes like inflammatory response, senescence, metabolism and tumorigenesis . In CRC, the overexpression of SIRT1 and it is colocalization with CD133, considered as a current universal marker to identify colorectal cancer stem cells (CSCs) . Nevertheless, both Aurora kinases and SIRT1 have been regulated through the Wnt signaling pathway, which consists of the major components such as Adenomatous polyposis coli (APC), Glycogen synthase kinase 3 beta (GSK3β) and β-catenin. The APC is a considered as a tumor suppressor gene, which is an important component of the destruction complex in the Wnt signaling pathway . Besides, it prevents uncontrolled growth of the cells and a negative regulator to control β-catenin expression . Whereas, the GSK3β is a serine/threonine protein kinase family and it phosphorylates multiple substrates, which are involved in regulation of protein synthesis, cell proliferation, differentiation and microtubule dynamics . Consecutively, the β-catenin is cell–cell adhesion and gene transcription protein that can be classified into cytoplasmic or nuclear-β-catenin. It is involved in proliferation, differentiation, migration, survival and angiogenesis by regulation of APC . Therefore, this review mainly targeting the interaction on molecular signaling mechanism of the Wnt regulation pathway with SIRT1 and Aurora kinases, is the best way to target cancer cells.