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In the last decade, an increasing interest in compounds containing pyrazolo[4,3- e ][1,2,4]triazine moiety is observed. Therefore, the aim of the research was to synthesise a novel sulphonyl pyrazolo[4,3- e ][1,2,4]triazines ( 2a , 2b ) and pyrazolo[4,3- e ]tetrazolo[1,5- b ][1,2,4]triazine sulphonamide derivatives ( 3a , 3b ) to assess their anticancer activity. The MTT assay showed that 2a , 2b , 3a , 3b have stronger cytotoxic activity than cisplatin in both breast cancer cells (MCF-7 and MDA-MB-231) and exhibited weaker effect on normal breast cells (MCF-10A). The obtained results showed that the most active compound 3b increased apoptosis via caspase 9, caspase 8, and caspase 3/7. It is worth to note that compound 3b suppressed NF-κB expression and promoted p53, Bax, and ROS which play important role in activation of apoptosis. Moreover, our results confirmed that compound 3b triggers autophagy through increased formation of autophagosomes, expression of beclin-1 and mTOR inhibition. Thus, our study defines a possible mechanism underlying 3b -induced anti-cancer activity against breast cancer cell lines.

Breast cancer is a major malignancy among women, characterized by a high mortality rate. The available literature evidence indicates that selenium, as a trace element, has chemopreventive properties against many types of cancer; as such, compounds containing it in their structure may potentially exhibit anticancer activity. Accordingly, we have undertaken a study to evaluate the effects of novel selenoesters (EDAG-1, -7, -8, -10) on MCF-7 and MDA-MB-231 breast cancer cells. Our analysis included investigations of cell proliferation and viability as well as cytometric determinations of apoptosis/autophagy induction, changes in mitochondrial membrane polarity (ΔΨ m ), caspase 3/7, 8, and 9 activities, and Bax, Bcl-2, p53, Akt, AMPK, and LC3A/B proteins. The obtained data revealed that the tested derivatives are highly cytotoxic and inhibit cell proliferation even at nanomolar doses (0.41-0.79 µM). Importantly, their strong proapoptotic properties (↑ caspase 3/7) are attributable to the effects on both the extrinsic (↑ caspase 8) and intrinsic (↓ ΔΨ m and Bcl-2, ↑ Bax, p53, and caspase 9) pathways of apoptosis. Moreover, the tested compounds are autophagy activators (↓ Akt, ↑ autophagosomes and autolysosomes, AMPK, LC3A/B). In summary, the potent anticancer activity suggests that the tested compounds may be promising drug candidates for future breast cancer therapy.

The study aims to synthesize a novel bis(thiosemicarbazone) derivative based on platinum (thioPt) and evaluate its anticancer properties against MFC-7 and MDA-MB-231 breast cancer cells. A new platinum complex was synthesised by reacting K 2 PtCl 4 with 2,2'-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbothioamide) in ethanol in the presence of K 2 CO 3 . In the obtained complex, the platinum atom is coordinated by a conjugated system = N-NC-S-The structures of the new compound were characterised using NMR spectroscopy, HR MS, IR, and X-ray structural analysis. The obtained results of the cytotoxicity assay indicate that compound thioPt had potent anticancer activity (MCF-7: 61.03 ± 3.57 µM, MDA-MB-231: 60.05 ± 5.40 µM) with less toxicity against normal MCF-10A breast epithelial cells, even compared to the reference compound (cisplatin). In addition, subsequent experiments found that thioPt induces apoptosis through both an extrinsic (↑caspase 8 activity) and intrinsic (↓ΔΨ m ) pathway, which ultimately leads to an increase in active caspase 3/7 levels. The induction of autophagy and levels of proteins involved in this process (LC3A/B and Beclin-1) were examined in MCF-7 and MDA-MB-231 breast cancer cells exposed to tested compounds (thio, thioPt, cisPt) at a concentration of 50 µM for 24 h. Based on these results, it can be concluded that thio and thioPt do not significantly affect the autophagy process. This demonstrates their superiority over cisplatin, which can stimulate cancer cell survival through its effect on stimulation of autophagy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Gastric cancer (GC) is a multifactorial disease with high mortality. Anti-HER2 therapy is a promising strategy in GC treatment and trastuzumab was approved by FDA (Food and Drug Administration) as the first and the second line of treatment of the disease., Purpose: The aim of the study was to examine the effectiveness of a combination of etoposide with trastuzumab or pertuzumab in AGS gastric cancer cells and breast cancer cells such as MCF-7, MDA-MB-231 and HCC1954., Methods and Findings: The cytotoxic effects of the tested compounds against gastric and breast cancer cells were checked by MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) assay. The anti-proliferative potential was analyzed by the incorporation of [3H]-thymidine into DNA. Fluorescent microscopy and flow cytometry was used to demonstrate the effect of the compounds on apoptosis. The mitochondrial membrane potential, and the activity of caspase-8 and caspase-9 were assessed. Autophagosomes and autolysosomes formation was checked by flow cytometry. The concentrations of Beclin-1, LC3A and LC3B were performed using ELISA. The expression of LC3A/B was also determined. The results from our study proved that the combination of etoposide with anti-HER2 antibodies was not cytotoxic against breast cancer cells, whereas the combination of etoposide with anti-HER2 antibodies decreased viability and DNA biosynthesis in gastric cancer cells. The interaction of etoposide with pertuzumab or trastuzumab induced programmed cell death via extrinsic and intrinsic apoptotic pathways in AGS gastric cancer cells, but did not affect autophagy, where a decrease of Beclin-1, LC3A and LC3B was observed in comparison with the untreated control., Conclusions: The study demonstrated that etoposide (12.5 μM) with pertuzumab represent a promising strategy in gastric cancer treatment, but further in vivo examinations are also required., Competing Interests: The authors have declared that no competing interests exist.

Six novel compounds of platinum(II) with pyrazole derivatives PtPz1-PtPz6 were synthesised and characterised (PtPz1 - [Pt 2 N-hydroksymethyl-3,5-dimethylpyrazole 4 (berenil) 2 ]Cl 4 ; PtPz2 - [Pt 2 3,5-dimethylpyrazole 4 (berenil) 2 ]Cl 4 ; PtPz3 - [Pt 2 3,4-dimethylpyrazole 4 (berenil) 2 ]Cl 4 ; PtPz4 - [Pt 2 pyrazole 4 (berenil) 2 ]Cl 4 ; PtPz5- [Pt 2 5-methylpyrazole 4 (berenil) 2 ]Cl 4 ; PtPz6 - [Pt 2 N-ethylpyrazole 4 (berenil) 2 ]Cl 4 ). The cytotoxic activity of these complexes against MCF-7 and MDA-MB-231 breast cancer cell lines was determined using the MTT assay. Evaluation of apoptosis induction was done with the Annexin V-fluorescein isothiocyanate/propidium iodide assay. In addition, using a flow cytometer, we determined the influence of test compounds on the cell cycle and caspase-3, -8, and -9 activity. The obtained results of caspase activity were confirmed by cell imaging. Moreover, using the flow cytometer, the effects of the test compounds on mitochondrial potential change were assessed. The test results showed that novel pyrazole-platinum(II) complexes exhibited stronger anti-proliferative activity against two breast cancer cell lines than reference cisplatin. Compounds PtPz1, PtPz2, and PtPz3 with methyl substituents at the pyrazole ring showed stronger activity than pyrazole or ethylpyrazole containing complexes. Studies have shown that inhibition of cell survival occurs by arresting the G1 cell cycle and inducing apoptosis. Our analysis associated with the response of MCF-7 and MDA-MB-231 cells to treatment with PtPz1-PtPz6 showed that it leads the cells through the external and intrinsic (mitochondrial) apoptotic pathway via indirect DNA damage.

In this study, we evaluated the cytotoxic activity and antiproliferative potency of novel octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives (1-7) in MCF-7 and MDA-MB-231 breast cancer cell lines. Annexin V binding assay and disruption of the mitochondrial potential were performed to determine apoptosis. The activity of caspases 3, 8, 9, and 10 was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Our study demonstrated that the most active compounds in both analyzed breast cancer cell lines were compounds 3 and 4. We also observed that all compounds induced apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. Our study revealed that the novel compounds in group of diisoquinoline derivatives are promising candidates in anticancer treatment by activation of both extrinsic and intrinsic apoptotic pathways.

The aim of the present study was to examine the impact of a four platinum complexes of formula [Pt2L4(berenil)2]Cl4 where L is 3-ethylpyridine (Pt10), 3-(n-butyl)pyridine (Pt11), 4- ethylpyridine (Pt12) and 4-(t-butyl)pyridine (Pt13) on viability of Ishikawa endometrial cancer cells using the MTT assay and inhibition of [3H]thymidine incorporation into DNA. Our results confirm that compounds Pt10-Pt13 are more potent antiproliferative agents than cisplatin in endometrial cancer cells. Moreover, it was shown that all examined compounds Pt10-Pt13 inhibit collagen biosynthesis in neoplastic cells stronger than cisplatin. Flow cytometric analysis after annexin V-FITC and propidium iodide staining confirmed also that apoptosis was the main response of Ishikawa endometrial cancer cells to Pt10-Pt13 treatment. Our results suggest that apoptosis of Ishikawa endometrial cancer cell lines in the presence of Pt10-Pt13 follows the mitochondrial pathway, with the decrease in mitochondrial membrane potential and activation of caspase 9, as well as by the external pathway with the significant increase in FADD protein expression and caspase 8.

The current work investigates the influence of novel dinuclear platinum(II) compounds of structure: Pt2(3-ethylpyridine)4(berenil)2 (Pt10) and Pt2(3-butylpyridine)4(berenil)2 (Pt11) on growth and viability of MDA-MB-231 and MCF-7 breast cancer cells as well as their putative mechanism of cytotoxicity. Evaluation of the cytotoxicity of Pt10 and Pt11 employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that these compounds were more potent antiproliferative agents than cisplatin. In our study the induction of apoptosis by Pt10 and Pt11 in human breast cancer cells was confirmed by several biochemical markers, such as: phosphatidylserine externalization, loss of mitochondrial membrane potential ΔΨm, caspase-3, -8, -9 activity, and DNA degradation. Pt10 and Pt11 induce apoptosis of breast cancer cells via mechanisms dependent on caspases activation and associated with mitochondrial membrane potential disruption., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Evaluation of the cytotoxicity of a novel dinuclear platinum(II) complex of formula Pt(2)(2-picoline)(4)(berenil)(2) employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that the complex was more of a potent antiproliferative agent than cisplatin. The DNA-binding ability of Pt(2)(2-picoline)(4)(berenil)(2) estimated by an ethidium displacement assay indicated that the complex showed strong specificity for AT base pairs in the minor groove of DNA. Our study showed that Pt(2)(2-picoline)(4)(berenil)(2) was a potent catalytic inhibitor of topoisomerase II in opposition to cisplatin. Pt(2)(2-picoline)(4)(berenil)(2) was found to be a more active inhibitor of collagen biosynthesis than cisplatin. The up regulation of beta(1)-integrin and insulin-like growth factor I (IGF-I) receptor expression by the complex was shown to be accompanied by an increase in the expression of mitogen activated protein kinases in breast cell lines. The phenomenon was related to the increased expression of nuclear factor-kappaB (NuF-kappaBeta) by Pt(2)(2-picoline)(4)(berenil)(2) as shown by the Western immunoblot analysis. Flow cytometric analysis and a fluorescent microscopy assay demonstrated that cell death appeared to result from apoptosis, with the possibility of secondary necrosis. The data presented suggested that Pt(2)(2-picoline)(4)(berenil)(2) impaired growth and metabolism of breast cancer cells more efficiently than cisplatin. These results indicated also the different properties of Pt(2)(2-picoline)(4)(berenil)(2) and cisplatin., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)