Novel methylselenoesters induce programed cell death via entosis in pancreatic cancer cells

Redox active selenium (Se) compounds have gained substantial attention in the last decade as potential cancer therapeutic agents. Several Se compounds have shown high selectivity and sensitivity against malignant cells. The cytotoxic effects are exerted by their biologically active metabolites, with methylselenol (CH3SeH) being one of the key executors. In search of novel CH3SeH precursors, we previously synthesized a series of methylselenoesters that were active (GI50 < 10 µM at 72 h) against a panel of cancer cell lines. Herein, we refined the mechanism of action of the two lead compounds with the additional synthesis of new analogs (ethyl, pentyl, and benzyl derivatives). A novel mechanism for the programmed cell death mechanism for Se-compounds was identified. Both methylseleninic acid and the novel CH3SeH precursors induced entosis by cell detachment through downregulation of cell division control protein 42 homolog (CDC42) and its downstream effector β1-integrin (CD29). To our knowledge, this is the first time that Se compounds have been reported to induce this type of cell death and is of importance in the characterization of the anticancerogenic properties of these compounds

A diphenyldiselenide derivative induces autophagy via JNK in HTB-54 lung cancer cells

Symmetric aromatic diselenides are potential anticancer agents with strong cytotoxic activity. In this study, the in vitro anticancer activities of a novel series of diarylseleno derivatives from the diphenyldiselenide (DPDS) scaffold were evaluated. Most of the compounds exhibited high efficacy for inducing cytotoxicity against different human cancer cell lines. DPDS 2, the compound with the lowest mean GI50 value, induced both caspase-dependent apoptosis and arrest at the G0/G1 phase in acute lymphoblastic leucemia CCRF-CEM cells. Consistent with this, PARP cleavage; enhanced caspase-2, -3, -8 and -9 activity; reduced CDK4 expression and increased levels of p53 were detected in these cells upon DPDS 2 treatment. Mutated p53 expressed in CCRF-CEM cells retains its transactivating activity. Therefore, increased levels of p21CIP1 and BAX proteins were also detected. On the other hand, DPDS 6, the compound with the highest selectivity index for cancer cells, resulted in G2/M cell cycle arrest and caspase-independent cell death in p53 deficient HTB-54 lung cancer cells. Autophagy inhibitors 3-methyladenine, wortmannin and chloroquine inhibited DPDS 6-induced cell death. Consistent with autophagy, increased LC3-II and decreased SQSTM1/p62 levels were detected in HTB-54 cells in response to DPDS 6. Induction of JNK phosphorylation and a reduction in phospho-p38 MAPK were also detected. Moreover, the JNK inhibitor SP600125-protected HTB-54 cells from DPDS 6-induced cell death indicating that JNK activation is involved in DPDS 6-induced autophagy. These results highlight the anticancer effects of these derivatives and warrant future studies examining their clinical potential

New symmetrical quinazoline derivatives selectively induce apoptosis in human cancer cells

In the search of new symmetrical derivatives with anticancer activity, we have looked for novel compounds able to induce a selective proapoptotic mechanism in cancer cells. The potential antitumoral activity of several quinazoline derivatives was evaluated in vitro examining their cytotoxic effects against human breast, colon and bladder cancer cell lines. The IC(50) value of the compounds that showed cytotoxic activity was calculated. These compounds were tested for their ability to induce caspase-3 activation and nuclear chromatin degradation. Non-tumoral human cell lines were used to test the selectivity of the cytotoxic compounds against cancer cells. Several compounds showed no cytotoxicity in these cell lines. Finally, JRF12 (2,4-dibenzylaminoquinazoline) was chosen as the best candidate and its mechanism of action was studied in more detail. A time dependent evaluation of apoptosis was performed in the three cancer cell lines, followed by an evaluation of the cell cycle regulation involvement that showed a decrease of cells in G(1) phase and increase of cells in G(2) phase before cell death. 2,4-dibenzylaminoquinazoline treatment produces few changes in the expression of genes as evaluated by using oligonucleotide microarrays and Q-RT-PCR assays. In conclusion, 2,4-dibenzylaminoquinazoline is a promising anticancer drug showing cytostatic and apoptotic effects mainly in a transcription independent manner

Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic

The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032

Diseño, síntesis y evaluación biológica de nuevos derivados de pirido[2,3-d] pirimidina y quinazolina con actividad antitumoral. Valoración de su capacidad antimetastática

The disease of cancer has been ranked as a major health burden. Pyrido[2,3-d]pyrimidine and quinazoline derivatives have attracted attention due to their broad range of pharmacological activities: antifungal, antimalarial, anti-inflammatory, anticonvulsant, antibacterial, antihypertensive, and their anticancer activity is one of the most promising aspects as they act through multiple targets. Based on these observations and considering our experience with these heteroaromatic rings, we have synthesized 57 novel 2.4-disubstituted quinazoline and Pyrido[2,3-d]pyrimidine derivatives. These compounds have been screened in vitro against five tumoral cell lines – prostate (PC-3), leukemia (CCRF-CEM), colon (HT-29), lung (HTB-54) and breast (MCF-7) – and two cell lines derived from non-malignant cell lines, one mammary (184B5) and one from bronchial epithelium (BEAS-2B). MCF-7 and HTB-54 have been the most sensitive cell lines with GI50 values below 10 µM for eleven and ten compounds, respectively. To compounds (I.3 and IV.14) evoke a marked cytotoxic effect in all cell lines tested and one compound, IV.7, has been potent and selective against MCF-7. A preliminary study into the mechanism of the potent derivatives I.3, IV.7 andIV.14 indicates that the cytotoxic activities of these compounds might be mediated by inducing cell death without modifications on cell cycle. Moreover, the signalling pathway implicated in the cell death observed upon treatment in MCF-7 cells by compound IV.14 could be AKT/S6 ribosomal/m-TOR. The lead compounds induce inhibition of cell migration in MDA-MB-231 cells and in this inhibition of migration the kinases AKT, S6 ribosomal, FAK and SRC are not implicated

Diseño, síntesis y evaluación biológica de nuevos derivados organoselénicos con actividad citotóxica y apoptótica

El objetivo general de este trabajo es verificar que la asociación, en moléculas de nueva síntesis, de elemento selenio, simetría molecular en un sentido amplio y determinados grupos químicos, constituyendo un modelo estructural definido, puede conferir a dichas moléculas actividad antitumoral

Design, synthesis and biological evaluation of novel methyl selenoesters as antiproliferative and cytotoxic agents

In this work, an innovative series of methylselenoesters as methylselenol precursors has been designed, synthesized and evaluated. The chemical characteristics of the carbonyl-selenium bond allow a nucleophilic attack that can render methylselenol, a key molecule in selenium biological activity. The scaffolds were chosen among carboaromatic and heteroaromatic rings with reported antitumoral activity to improve the action of methylselenol and to provide enough chemical variety to modulate the strength of the carbonyl-selenium bond, therefore hindering or facilitating a nucleophilic attack, i.e., by water. The release rate of methylselenol was determined, as well as the cytotoxic activity of the compounds against a panel of cancer cell lines. The leader compounds were further investigated to determine their mechanism of action as entosis inducers, which had not been previously described. In addition, other selenium compounds were evaluated. Methylseleninic acid and selenite were tested in a leukemic cell line to explore their genome-wide epigenetic effect. Furthermore, these compounds were also evaluated as immune regulators in the context of ovarian cancer

Design, synthesis and biological evaluation of new organoseleno compounds as cytotoxic and leishmanicidal agents

A series of thirty-three novel selenium-containing compounds with potential antitumoral and/or leishmanicidal activity have been synthesized and evaluated in this work. Numerous preclinical studies have proven the strong dependency between chemical form of Se and its biological activity. Taking into account the experience of our research group in this field, we selected two leader compounds bis(4- aminopheny)diselenide and 4-aminophenyselenocyanate to design second generation derivatives. The structural modifications performed on these core structures had the aim of improving their activity and selectivity. The novel derivatives containing the functionalities diselenide and selenocyanate have been tested against a panel of several human cancer cell lines and two cell lines derived for non-malignant tissue. Once obtained their cytotoxic profiles and selectivity, derivatives were ranked to stablish the hit compounds. The most promising molecules have been selected to preform further biological studies relative to cell death and cell cycle status in order to elucidate their mechanism of action. Moreover, the development of new methodologies that enable the possibility to study the glutathione peroxidase mimetic ability of new derivatives has been explored. The leishmanicidal activity of the synthesized Se-containing compounds was analyzed against Leishmania Infantum axenic amastigotes. In order to assess selectivity cytotoxicity against THP-1 cells was tested. According to potency and selectivity six derivatives were selected to further study the mechanism of action by which they cause their effect. Also, we decided to explore the ability of these compounds to inhibit Trypanothione Reductase, enzyme that plays a crucial role in the survival of the parasite. In addition, their stability under formulation conditions such as temperature, acid or alkaline conditions have been evaluated. The objective was to predict the nondesired transitions or degradation processes that may occur along the pharmaceutical manufacturing processing