Preliminary evaluation of antiproliferative and apoptotic activities of novel indolin-2-one derivatives.

Indole-based agents are frequently used in targeted or supportive therapy of several cancers. In this study, we investigated the anticancer properties of originally synthesized novel indolin-2-one derivatives (6a-d) against Malignant Mesothelioma, Breast cancer, and Colon Cancer cells. Our results revealed that all derivatives were effectively delayed cell proliferation by inhibiting the ERK1/2, AKT, and STAT3 signaling pathways in a concentration-dependent manner. Additionally, these variants induced cell cycle arrest in the S phase, accompanied by elevated levels of p21 and p27 expressions. Derivatives also initiated mitochondrial apoptosis through the upregulation of Bax and downregulation of Bcl-2 proteins, leading to the activation of caspase 3 and PARP cleavage in exposed cells. Remarkably, three of the indolin-2-one derivatives displayed significant selectivity towards Breast and Colon Cancer cells, with compound 6d promising as the most potent and wide spectral one for all cancer cell lines.

Anticarcinogenic effects of halofuginone on lung-derived cancer cells.

Malignant mesothelioma is a rare but aggressive form of malignancy, which is difficult to diagnose and is resistant to current chemotherapeutic treatment options. Molecular techniques have been used to investigate the mechanisms of action and the beneficial therapeutic effects of halofuginone (HF) in several cancers but not malignant mesotheliomas. In this study, the antiproliferative and apoptotic effects of HF were investigated through its ability to deregulate EGFR downstream signalling cascade proteins in the pathologically aggressive malignant mesothelioma and non-small-cell lung cancer cells. We showed that administration of HF at nanomolar concentrations induced a dose-dependent reduction in the viability of cancer cells, made cell cycle arrest, inhibited proliferation of cancer cells via STAT3 and ERK1/2 pathways and triggered the apoptotic cascade via p38MAPK. We demonstrated that the apoptotic cell death mechanism was mediated by enhanced activation of caspase-3 and concomitant PARP cleavage, downregulation of Bcl-2 and upregulation of Bax in both malignant mesothelioma and lung cancer cells. In particular, we demonstrated that cancer cells were more sensitive to HF treatment than normal mesothelial cells. Taken together, this study suggests that HF exerts its anticancer effects in lung-derived cancers by targeting signal transduction pathways mainly through deregulation of ERK1/2, STAT3 and p38MAPK to reduce cancer cell viability, induce cell cycle arrest and apoptotic cell death. Thus, HF might be considered as a potential agent against malignant mesothelioma and/or lung cancer cells.

Investigation of potent anticarcinogenic activity of 1, 3-diarylpyrazole acrylamide derivatives in vitro.

OBJECTIVES: Pyrazole derivatives are pharmacologically powerful agents pointing at new horizons in the development of anticancer therapies. In this study, anticarcinogenic potential of a series of pyrazole-acrylamide derivatives has been investigated in mesothelial, malignant mesothelioma and lung cancer cell lines. METHODS: The effect of compounds on the viability of cells and the distribution of cell cycle were examined through MTS assay and PI staining, respectively. Apoptosis was evaluated via caspase-3 enzymatic assay and AO/EB staining. Proteins involved in proliferation, survival and apoptosis were analysed by immunoblotting. KEY FINDINGS: Twelve compounds of 21 (4a-4v) reduced the viability of cells but, only the subset of five (4f, 4i, 4j, 4k and 4v) induced the caspase-3 activity. Among five, only one compound (4k) significantly suppressed phosphorylation and expression of ERK1/2 and AKT proteins in 24 h. Exposing cancer cells to successive concentrations of 4k gave rise to dose- and time-dependent G2/M phase arrest and apoptosis. CONCLUSIONS: 4k has revealed its potent antiproliferative activity by decreasing viability and inhibiting proliferation and survival signals of cancer cells. Moreover, 4k has exposed cytostatic and apoptotic effect especially, on cancer cells. Therefore, it may be necessary to examine the biological actions of 4k in vivo as well.