Dados do Trabalho

Título

Evaluation of the antitumor activity of hybrid drugs (Chalconas & Quinazolines) in pacreatic cancer cell lines

Introdução

The use of hybrid molecules in cancer therapy attempts to extract the pharmacological potential of two molecules, which will act synergistically, with lower doses and with less chances of tumor pharmacological resistance effect. In this project, 15 novel hybrid molecules derived from chalcones and quinazolines were evaluated for their in vitro activity in pancreatic tumor cells lines.

Objetivo

Evaluate the antitumor potential of hybrid molecules, and to analyze the influence of candidate hybrid molecules on cell cycle inhibition and death.

Métodos

15 hybrid molecules were exposed to the pancreatic tumor cells PANC-1, BXPC-3, MiaPaca-2 and HFF-1 healthy fibroblast, cultured in DMEM or RPMI complete medium. The levels of growth inhibition (GI), cell viability and IC50 were obtained using protocols adapted from the National Cancer Institute (NCI) - ONE DOSE and FIVE DOSE screening, by MTS calorimetric assay. Following the determination of IC50 values for the most promising molecules, we proceeded Following the determination of IC50 values for the most promising molecules, we proceeded the Selectivity Index (SI), cell cycle and cellular death were analyzed by flow cytometry. As negative and positive controls, DMSO and the 5-fluorouracil (5FU) were used, respectively.

Resultados

The initial analysis (ONE DOSE screening), in which the tumor and non-tumor (HFF-1) cell lines were treated with the 15 hybrid molecules at 10mM, revealed that the molecules R2, R3, R6 and R14 were the most selective for tumor cell lines, displayed low GI levels for HFF-1 (below 50%), while for tumor cell lines this value was above 50%. The FIVE DOSE screening step revealed that the R6 molecule was more selective, with IS of 2.25 and IC50 of 7.74 mM for the PANC-1 cell line characterized as more sensitive. Flow cytometry showed that the R14 molecule increased the rates of necrosis and late apoptosis (72h), when compared to the negative control.

Conclusões

The screening steps of the candidate hybrid molecules have been completed, and according to our results 3 hybrid molecules (R2, R6 and R14), will proceed to the further analysis of cell cycle inhibition due to low GI in healthy cells, and reduced viability of pancreatic tumor celllines when compared to 5-FU.

Palavras-chave

Hybrid drugs, Pancreatic Cancer, Chalcones, Quinazolines, preclinical trials.

Financiador do resumo

Financial Support:: CNPQ; PAIP (Barretos cancer hospital); FAPERGS

Área

Estudo Clínico - Tumores do Aparelho Digestivo Alto