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

• Published in: Biomolecules (Basel, Switzerland) Vol. 12; no. 10; p. 1490
• Main Authors: Duarte, Diana, Nunes, Mariana, Ricardo, Sara, Vale, Nuno
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.10.2022; MDPI
• Subjects: 5-Fluorouracil; Adenocarcinoma; Adenosine Diphosphate; antimalarial drugs; Antimalarials; Antimalarials - pharmacology; Antimalarials - therapeutic use; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Artesunate; Artesunate - pharmacology; Artesunate - therapeutic use; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Benztropine - pharmacology; Benztropine - therapeutic use; Biomarkers; Biosafety; Breast cancer; Breast Neoplasms - metabolism; Cancer therapies; cancer therapy; Cell culture; Cell cycle; Cell Line, Tumor; Central nervous system; Central nervous system agents; Chemotherapy; Chloroquine; Chloroquine - pharmacology; CNS drugs; Colon cancer; Colonic Neoplasms - drug therapy; Colorectal cancer; Containment of Biohazards; Cytology; Cytotoxicity; Dosage and administration; Doxorubicin; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; drug combination; Drug interactions; drug repurposing; Drug resistance; Drug Resistance, Neoplasm; Drug therapy; Drug therapy, Combination; Enzymes; Evaluation; Female; Fetuses; Fibroblasts; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Fluoxetine; Fluoxetine - pharmacology; Fluoxetine - therapeutic use; Fluphenazine; Fluphenazine - pharmacology; Fluphenazine - therapeutic use; Glycoproteins; Humans; Immunohistochemistry; Ki-67 Antigen - metabolism; Malaria; MCF-7 Cells; Medical prognosis; Methods; Michigan; Multidrug resistance; NF-kappa B - metabolism; NF-κB protein; P-Glycoprotein; Paclitaxel; Paclitaxel - pharmacology; Palmitoyl-(protein) hydrolase; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; PPT1; Proteins; Ribose; Ribose - pharmacology; Ribose - therapeutic use; Sertraline; Sertraline - pharmacology; Sertraline - therapeutic use; Thioridazine; Thioridazine - pharmacology; Thioridazine - therapeutic use; Michigan; Portugal; United States > US; CNS drugs; PPT1; cancer therapy; antimalarial drugs; drug repurposing; drug combination
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom12101490

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 (IC ). 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.