RESUMO
In recent decades, indolocarbazole glycosides containing sugar moieties have attracted attention due to their diverse anti-tumor activities. In the present study, a series of new indolo [2,3-a]pyrrolo [3,4-c]carbazole derivatives were synthesized for the first time. First of all, we have shown that compound 6e (LCS1269) had the most pronounced effect on inhibiting tumor growth in the transferable solid and non-solid murine tumors as compared with other synthesized indolocarbazole derivatives. The results of the in vivo nude mice xenoraft study also confirmed that LCS1269 treatment strongly suppressed the growth of human colon cancer SW620 xenografts. It is important to note that the antiproliferative activity of LCS1269 against three human cancer cell lines (MCF-7, HCT-116 and A549) was considerably higher than that against the non-tumor cell lines (immortalized breast cells and normal embryonic fibroblasts). Furthermore, the treatment of MCF-7, HCT-116 and A549 cells with LCS1269 caused the statistically significant inhibition of anchorage-dependent and anchorage-independent colony formation. We further revealed that LCS1269 treatment of investigated human cancer cells resulted in the DNA damage and G2/M cell cycle arrest followed by the decrease of mitochondrial membrane potential with subsequent initiation of intrinsic apoptosis and the triggering of senescence via p53-dependent mechanisms. In addition, our western blotting findings and molecular docking data suppose that LCS1269 could at least partially attenuate cancer cells growth by modulation of AKT/mTOR/S6K and ERK signaling pathways. Therefore, we concluded that LCS1269 might be the promising compound for implementation and probable use in the clinical practice.
Assuntos
Antineoplásicos , Neoplasias , Animais , Antineoplásicos/farmacologia , Apoptose , Carbazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Dano ao DNA , Glicosídeos/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Semi-synthetic A-cycle modified triterpenic derivatives with A-cycle condensed with a heterocyclic fragment (compound 1) and fragmented A-ring (compound 2) were tested for cytotoxicity against several tumor cell cultures and doxorubicin (Dox)-resistant cell lines. The equal cytotoxicity of the tested compounds to the parental tumor cell lines (HBL-100, K562) and their resistant subclones (HBL-100/Dox, K562/i-S9) was revealed. The overexpression of ABCB1 (MDR1) gene and P-glycoprotein (P-gp) was confirmed for both resistant subclones of tumor cells. Compounds 1 and 2 were shown to inhibit the ABC-transporter gene expression (MDR1, MRP, MVP, and BCRP) and the transport of well-known P-gp substrate Rhodamine 123 from resistant cells. The docking of triterpenoids 1 and 2 into the drug binding site of P-gp revealed a similarity between the conformation of the tested triterpenoids and that of classical inhibitor verapamil, thus assuming these compounds to be more likely the inhibitors than the substrates of P-gp. Any tested triterpenic derivatives, when combined at non-toxic concentrations with doxorubicin, improved cytotoxic effect of the therapeutic drug against resistant subclones of tumor cells.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Triterpenos/química , Triterpenos/farmacologia , Linhagem Celular Tumoral , Humanos , Relação Estrutura-AtividadeAssuntos
Biomarcadores Tumorais/biossíntese , Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/metabolismo , Proteínas de Neoplasias/biossíntese , Sindecana-1 , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Feminino , Humanos , Masculino , Mieloma Múltiplo/patologiaRESUMO
The regulation of vascular endothelial growth factors C (VEGF-C) and D (VEGF-D), and their receptor VEGFR3 gene and protein expression by all-trans-retinoic acid (atRA) in A549 lung cancer cells, was investigated. We showed that atRA treatment increased VEGF-C, VEGF-D, and VEGFR3 protein and mRNA contents in dose-dependent manner. atRA-mediated increase of both ligands and receptor expression correlated with the elevated level of retinoic acid receptor α (RARα) expression, while the level of another atRA receptor, peroxisome proliferator-activated receptor ß/δ (PPARß/δ), was decreased. We demonstrated that the classical counterpart of RARα, retinoid X receptor α (RXRα), was down-regulated in both cytoplasm and nucleus of A549 cells upon atRA addition. On the contrary, the nuclear quantity of another possible RARα counterpart, transcription factor Sp1, was increased after atRA treatment.