Michigan Cancer Foundation-7 Breast Research Articles

Combination of Antimalarial and CNS Drugs with Antineoplastic Agents in MCF-7 Breast and HT-29 Colon Cancer Cells: Biosafety Evaluation and Mechanism of Action.

Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the combinations of doxorubicin (DOX) + artesunate, DOX + chloroquine, paclitaxel (PTX) + fluoxetine, PTX + fluphenazine, and PTX + benztropine induce significant cytotoxicity in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found that 5-FU + thioridazine and 5-fluorouracil (5-FU) + sertraline can synergistically induce a reduction in the viability of human colorectal adenocarcinoma cell line (HT-29). In this study, we aim to (1) evaluate the biosafety profile of these drug combinations for non-tumoral cells and (2) determine their mechanism of action in cancer cells. To do so, human fetal lung fibroblast cells (MRC-5) fibroblast cells were incubated for 48 h with all drugs, alone and in combination in concentrations of 0.25, 0.5, 1, 2, and 4 times their half-maximal inhibitory concentration (IC50). Cell morphology and viability were evaluated. Next, we designed and constructed a cell microarray to perform immunohistochemistry studies for the evaluation of palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), and nuclear factor-kappa-B (NF-kB) p65 expression. We demonstrate that these combinations are cytotoxic for cancer cells and safe for non-tumoral cells at lower concentrations. Furthermore, it is also demonstrated that PPT1 may have an important role in the mechanism of action of these combinations, as demonstrated by their ability to decrease PPT1 expression. These results support the use of antimalarial and central nervous system (CNS) drugs in combination regimens with chemotherapeutic agents; nevertheless, additional studies are recommended to further explore their complete mechanisms of action.

Synthesis, X-Ray Crystal Structures, Biological Evaluation, and Molecular Docking Studies of a Series of Barbiturate Derivatives

A series of barbiturates derivatives synthesized and screened for different set of bioassays are described. The molecular structures of compounds5a,5d,and5fwere solved by single-crystal X-ray diffraction techniques. The results of bioassay show that compounds4a,4b,4c,4d,4e,4f, and4gare potent antioxidants in comparison to the tested standards, butylated hydroxytoluene (BHT), andN-acetylcysteine. Compounds4a–4e(IC50=101.8±0.8–124.4±4.4 μM) and4g(IC50=104.1±1.9 μM) were more potent antioxidants than the standard (BHT,IC50=128.8±2.1 μM). The enzyme inhibition potential of these compounds was also evaluated,in vitro, against thymidine phosphorylase,α-glucosidase, andβ-glucuronidase enzymes. Compounds4c,4h,4o,4p,4q, 5f,and5mwere found to be potentα-glucosidase inhibitors and showed more activity than the standard drug acarbose, whereas compounds4v,and5hwere found to be potent thymidine phosphorylase inhibitors, more active than the standard drug, 7-deazaxanthine. All barbiturates derivatives (4a–4x,4z,and5a–5m) were found to be noncytotoxic against human prostate (PC-3), Henrietta Lacks cervical (HeLa) and Michigan Cancer Foundation-7 breast (MCF-7) cancer cell lines, and 3T3 normal fibroblast cell line, except4ywhich was cytotoxic against all the cell lines.