4-Thiazolidinone derivative Les-3833 effectively inhibits viability of human melanoma cells through activating apoptotic mechanisms

Aim To evaluate cytotoxic action of 4-thiazolidinone derivative Les-3833 and study the mechanisms of its pro-apoptotic action toward human melanoma cells and human tumor cell lines of other tissue origin. Methods The effect of Les-3833 or doxorubicin on the viability of 9 cell lines was studied using MTT assay, while human melanoma cells of WM793 line were additionally examined using light and fluorescent microscopies for evaluating cytomorphological changes. The Western-blot and flow cytometric analyses were carried out to study signaling pathways of melanoma cell cycling and death. Results Les-3833 was the most efficient against melanoma cells. Its half maximal inhibitory concentration (IC50) was 0.22 μg/mL for WM793 cells and 0.3 μg/mL for SK-Mel- 28 melanoma cells. For human lung A549, breast MCF-7, colon HCT116, and ovarian SKOV3 carcinoma cell lines IC50 was in between 2.5 to >5.0 μg/mL. Les-3833 was relatively not toxic (IC50 > 5 μg/mL) for human embryonic kidney HEK293 cells. Results of Annexin V/PI staining of melanoma cells and activation of caspase 3, PARP, MAPK, and EndoG protein suggest apoptosis in Les-3833-treated cells. Les- 3833 also induced ROS production in melanoma cells and their arrest in G0/G1 phase of cell cycle. Conclusion Novel 4-thiazolidinone derivative Les-3833 is effective against human melanoma cells in vitro, and such effect is tumor specific since it is much less pronounced in human carcinoma and leukemia cells. In melanoma cells Les-3833 induces apoptosis (morphological changes and increased pro-apoptotic proteins), ROS production, and arrest in G0/G1 phase of cell cycle

Antineoplastic Activity of Water-Soluble Form of Novel Kinase Inhibitor 1-(4-Chlorobenzyl)-3-chloro-4-(3-trifluoromethylphenylamino)-1H-pyrrole-2,5-dione immobilized on Polymeric Poly(PEGMA-co-DMM) Carrier

The maleimide derivative 1-(4-chlorobenzyl)-3-chloro-4-(3-trifluoromethylphenylamino)-1H-pyrrole-2,5-dione (MI-1) was synthesized as inhibitor of several protein kinases, however, its application is hindered by its poor water solubility. In this study, the mechanisms of the antineoplastic action of MI-1 and its MI-1/M5 complex with M5 carrier (poly (PEGMA-co-DMM)) towards human colon carcinoma HCT116 cells were investigated by using the MTT and clonogenic assays, DNA intercalation with methyl green replacement, alkaline DNA comet assay, and Western-blot analysis. MI-1 compound and its MI-1/M5 complex possessed high toxicity towards colon (HCT116), cervical (HeLa) carcinoma cells and melanoma (SK-MEL-28) cells with GI50 value in a range of 0.75–7.22 µg/mL, and demonstrated high selectivity index (SI ˃ 6.9). The p53 status of colon cancer cells did not affect the sensitivity of these cells to the treatment with MI-1 and its MI-1/M5 complex. M5 polymer possessed low toxicity towards studied cells. The MI-1, MI-1/M5, and M5 only slightly inhibited growth of the pseudo-normal HaCaT and Balb/c 3T3 cell lines (GI50 ˃ 50 μg/mL). The MI-1 and its MI-1/M5 complex induced mitochondria-dependent pathway of apoptosis, damage of the DNA, and morphological changes in HCT116 cells, and affected the G2/M transition checkpoint. The MI-1 intercalated into the DNA molecule, while such capability of MI-1/M5 complex and M5 polymer was much lower. Thus, poly (PEGMA-co-DMM) might be a promising carrier for delivery of the maleimide derivative, MI-1, a novel kinase inhibitor, through improving its solubility in aqueous media and enhancing its antiproliferative action towards human tumor cells. Studies are in progress on the treatment of Nemeth-Kellner lymphoma (NK/Ly)-bearing mice with the MI-1 and MI-1/M5 complex

Antineoplastic Activity of Water-Soluble Form of Novel Kinase Inhibitor 1-(4-Chlorobenzyl)-3-chloro-4-(3-trifluoromethylphenylamino)-1<i>H</i>-pyrrole-2,5-dione immobilized on Polymeric Poly(PEGMA-<i>co</i>-DMM) Carrier

The maleimide derivative 1-(4-chlorobenzyl)-3-chloro-4-(3-trifluoromethylphenylamino)-1H-pyrrole-2,5-dione (MI-1) was synthesized as inhibitor of several protein kinases, however, its application is hindered by its poor water solubility. In this study, the mechanisms of the antineoplastic action of MI-1 and its MI-1/M5 complex with M5 carrier (poly (PEGMA-co-DMM)) towards human colon carcinoma HCT116 cells were investigated by using the MTT and clonogenic assays, DNA intercalation with methyl green replacement, alkaline DNA comet assay, and Western-blot analysis. MI-1 compound and its MI-1/M5 complex possessed high toxicity towards colon (HCT116), cervical (HeLa) carcinoma cells and melanoma (SK-MEL-28) cells with GI50 value in a range of 0.75–7.22 µg/mL, and demonstrated high selectivity index (SI ˃ 6.9). The p53 status of colon cancer cells did not affect the sensitivity of these cells to the treatment with MI-1 and its MI-1/M5 complex. M5 polymer possessed low toxicity towards studied cells. The MI-1, MI-1/M5, and M5 only slightly inhibited growth of the pseudo-normal HaCaT and Balb/c 3T3 cell lines (GI50 ˃ 50 μg/mL). The MI-1 and its MI-1/M5 complex induced mitochondria-dependent pathway of apoptosis, damage of the DNA, and morphological changes in HCT116 cells, and affected the G2/M transition checkpoint. The MI-1 intercalated into the DNA molecule, while such capability of MI-1/M5 complex and M5 polymer was much lower. Thus, poly (PEGMA-co-DMM) might be a promising carrier for delivery of the maleimide derivative, MI-1, a novel kinase inhibitor, through improving its solubility in aqueous media and enhancing its antiproliferative action towards human tumor cells. Studies are in progress on the treatment of Nemeth-Kellner lymphoma (NK/Ly)-bearing mice with the MI-1 and MI-1/M5 complex

Anticancer Activity Evaluation of New Thieno[2,3-d]pyrimidin-4(3H)-ones and Thieno[3,2-d]pyrimidin-4(3H)-one Derivatives

Anticancer screening of several novel thienopyrimidines has been performed. The thienopyrimidine derivatives were synthesized from available starting materials according to the convenient synthetic procedures using a one-pot solvent-free reaction which gave a wide access to thienopyrimidine-derivative production. The synthesized compounds were preselected via molecular docking to be tested for their anticancer activity in NCI 60 cell lines. It was observed that some compounds showed remarkable anticancer activity. It was found that the most active compound among thieno[2,3-d]pyrimidine-4(3H)-ones is 2-(benzylamino)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one, which possesses cytotoxic activity on almost all cancer cell lines with mean growth 51.01%, where the most sensitive was the melanoma cell line MDA-MB-435 with GP (Growth Percent) = &minus;31.02%. The patterns of structure&ndash;activity that are important for further optimization of the structure and the creation of more selective and active anticancer agents were proposed

Active compounds from Calendula officinalis flowers act via PI3K and ERK signaling pathways to offer neuroprotective effects against Parkinson's disease

Calendula officinalis flowers, associated with diverse biological effects, could be utilized as functional food ingredients to play a crucial role in human health. In this study, we examined the anti-PD activity of C. officinalis flower extracts and investigated their bioactive compounds and molecular mechanisms based on LC–MS/MS assay, bioinformatic exploration and in vitro treatment of SH-SY5Y cells. C. officinalis extracts exhibited significant positive effects on the length and fluorescence density of the dopaminergic neuron region in zebrafish larvae. At 10 μg/mL, the extract restored the length to 96.54% and fluorescence density to 87.77% of the control values, which was equivalent to the effect of a positive drug, indicating the extract's powerful potential to alleviate PD symptoms. Five active compounds, including chlorogenic acid, 3,4-dicaffeoylquinic acid (DA), rutin, isorhamnetin 3-O-glucoside (IG) and calenduloside E (CE) were identified in extracts by LC-QTOF-MS/MS. Hsp90α, PI3K and ERK were revealed as core targets of DA, IG and CE in relation to anti-PD activity. The compounds docked deeply within the pocket region of Hsp90α protein, and their binding energies (∆Gb) were −6.93 kcal/mol (DA), −6.51 kcal/mol (IG) and −3.03 kcal/mol (CE), respectively. Subsequently, they concurrently activated the PI3K/Akt signaling pathway and inhibited the ERK signaling pathway, thereby preventing neuronal death and alleviating neuronal degeneration. These compounds from C. officinalis could be potent nutraceutical agents with protective properties that may shield dopaminergic neurons against the damage caused by PD. Our findings provide a basis for utilizing the C. officinalis flowers in functional foods

The Chemical Inhibitors of Endocytosis: From Mechanisms to Potential Clinical Applications

Endocytosis is one of the major ways cells communicate with their environment. This process is frequently hijacked by pathogens. Endocytosis also participates in the oncogenic transformation. Here, we review the approaches to inhibit endocytosis, discuss chemical inhibitors of this process, and discuss potential clinical applications of the endocytosis inhibitors