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  • Cancer cells manifest characteristic abnormal growth propert

    2024-05-15

    Cancer mek162 manifest characteristic abnormal growth properties accompanying clonal evolution of cells displaying progressively increasing genomic instability capable of invasion and metastasis to distant organ sites. With the emerging knowledge about the role of known oncogene and tumor suppressor gene mediated pathways in deregulating the growth of cancer cells, novel chemotherapeutic agents targeting these pathways are being developed. Such therapeutic approaches are designed to disrupt the signaling networks involving the respective target genes which are aberrantly expressed to cause uncontrolled growth of the malignant cells. While these strategies have shown promise in the initial treatment outcomes, their long term efficacy remains questionable in many instances since prolonged exposure to a specific target inhibiting drug often leads to cancer cells rewiring the aberrantly expressing signaling events to continue proliferation in a deregulated manner. This becomes possible since signaling cascades determining the abnormal growth phenotype are not regulated by linear events but result from complex functional networks constituted of cross talking individual signaling pathways. It is therefore logical to expect that for cancer therapeutics to be maximally effective, multiple signaling pathways converging on the fundamental growth regulatory processes such as DNA replication and/or mitosis need to be targeted in a robust manner. It is noteworthy, in this context, that efficacy of most conventional and novel chemotherapeutic agents rests on the premise that cancer cells can be preferentially eliminated due to their persistent cycling nature by interfering with either their replication/repair of DNA or by disrupting the mitotic division process. Thus, among the commonly used drugs for cancer chemotherapy, agents such as fluoropyramidines, gemcitabine and topoisomerase inhibitors interfere with the DNA replication process while platinum analogues and cyclophosphamide introduce un-resolvable lesions into the replicating DNA of proliferating cells to induce cell death. Another group of effective drugs, which include taxanes, vinca alkaloids and epothilones causes growth inhibition and death of proliferating cells by disrupting the microtubule cytoskeleton essential for the mitotic cell division process [1]. However, given the fact that a host of normal cells continuously proliferate in adult tissues, it is not unexpected that cytotoxic drugs indiscriminately targeting proliferating cells inflict varying degrees of normal tissue damage and thus cause toxicity to the patients. Functional genomic data from tumors is proving helpful in alleviating the problem by identifying the putative therapeutic target proteins regulating cell cycle that are differentially expressed in tumors compared with the normal cells of the adult tissues. It is plausible that pharmaceutical targeting of such proteins would help the development of a new generation of effective therapeutic drugs that will have minimal host toxicity. These drugs while still interfering with the cell proliferation process would be expected to have a more selective effect on the tumors due to a preferential negative response of signal attenuation in the tumor cells compared with their normal counterparts [2]. Based on this rationale, proteins involved in the regulation of cell cycle [3] and cell cycle associated kinases [4], [5], expressing at abnormally high levels in tumors, have been proposed as promising novel targets for the development of anticancer drugs. In the recent past a number of inhibitors against new mitotic targets have indeed been rapidly moving into clinical trials [6]. Among the mitosis regulatory kinases, evolutionarily conserved family of serine/threonine kinases referred to as Aurora kinases has emerged as an exceptionally attractive target for anticancer drug discovery. The interest in designing drugs against Aurora kinase family members stems from the facts that these kinases, expressed at elevated levels in many human cancers, are not only vitally important regulators of mitosis but have also been shown to functionally interact with multiple critical oncoproteins and tumor suppressor proteins. Preclinical studies of Aurora kinase inhibitors have shown promising results and the ongoing phase I and II clinical trials for several of these as anticancer molecules have also yielded encouraging results so far.