Abstract
The Kinesins are proteins involved in several biological processes such as mitosis, intracellular transport, and microtubule movement. The mitotic process is allowed by the correct formation of the mitotic spindle which consists of microtubules originating from the spindle poles. In recent years, kinesin Eg5 inhibitors were studied as new chemotherapeutic drugs, due to the lack of side effects and resistance mechanisms. The aim of this work was to investigate the molecular signaling underlying the administration of novel kinesis Eg5 inhibitors in an in vitro model of gastric adenocarcinoma. Data obtained from analogues of K858 led us to select compounds 2 and 41, due to their lower IC50 values. The ability of kinesin inhibitors to induce apoptosis was investigated by evaluating Bax and Caspase-3 protein expression, evidencing that compound 41 and K858 markedly raise Bax expression, while only compounds 2 and 41 co-administrated with K858 trigger Caspase-3 activation. The inhibition of mitotic spindle was measured by β-tubulin immunofluorescence analysis revealing monopolar spindles formation in gastric cancer cells treated with compounds 2, 41, and K858. Nitric Oxide Synthase (NOS-2) and Matrix Metalloproteinase 9 (MMP-9) expression levels were measured finding a NOS-2-mediated downregulation of MMP-9 when compound 41 and K858 are co-administered. However, this is in contrast to what was reported by migration assay in which both novel compounds and K858 in monotherapy markedly reduce cell migration. This work remarks the importance of understanding and exploring the biological effects of different novel Eg5 kinesin inhibitors administered in monotherapy and in combination with K858 as potential strategy to counteract gastric cancer.
Highlights
Kinesin superfamily proteins, known as KIFs, are essential molecular motors that directionally transport several cargos, including membranous organelles, protein complexes, and mRNAs, and mediate cell division and microtubule movement
Our results show that a treatment of 24 h with compounds 2, 41 and K858, evidences different percentage of AGS cells with monoasters suggesting that the cells are sensitive to the different dose administrated
These targets were shown to be related to proliferation, invasion, angiogenesis, and metastasis of gastric cancer cells in vitro and in vivo, establishing a new scenario for the personalized therapy of this malignancy
Summary
Known as KIFs, are essential molecular motors that directionally transport several cargos, including membranous organelles, protein complexes, and mRNAs, and mediate cell division and microtubule movement. They are categorized into 14 subfamilies on the basis of sequence homology and classified as mitotic kinesins, which are involved in cell division, and non-mitotic kinesins, and are principally involved in intracellular transport. The mitotic spindle is a relevant target in cancer therapy and various drugs interfering with microtubule dynamics are approved for clinical use. Several compounds inhibiting mitotic kinesins such as Eg5 and centromere-associated protein E (CENPE) have been inserted in phase I and II of clinical trials either as monotherapies or in combination [3,4]
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