PMID- 36291699
OWN - NLM
STAT- MEDLINE
DCOM- 20221028
LR  - 20221228
IS  - 2218-273X (Electronic)
IS  - 2218-273X (Linking)
VI  - 12
IP  - 10
DP  - 2022 Oct 16
TI  - 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.
LID - 10.3390/biom12101490 [doi]
LID - 1490
AB  - 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(50)). 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.
FAU - Duarte, Diana
AU  - Duarte D
AUID- ORCID: 0000-0003-1420-5042
AD  - OncoPharma Research Group, Center for Health Technology and Services Research 
      (CINTESIS), Rua Doutor Placido da Costa, 4200-450 Porto, Portugal.
AD  - Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 
      4050-313 Porto, Portugal.
AD  - CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor 
      Hernani Monteiro, 4200-319 Porto, Portugal.
FAU - Nunes, Mariana
AU  - Nunes M
AD  - Differentiation and Cancer Group, Institute for Research and Innovation in Health 
      (i3S), University of Porto/Institute of Molecular Pathology and Immunology, 
      University of Porto (IPATIMUP), Rua Alfredo Allen 208, 4200-135 Porto, Portugal.
AD  - Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua 
      Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
FAU - Ricardo, Sara
AU  - Ricardo S
AUID- ORCID: 0000-0003-4091-2226
AD  - Differentiation and Cancer Group, Institute for Research and Innovation in Health 
      (i3S), University of Porto/Institute of Molecular Pathology and Immunology, 
      University of Porto (IPATIMUP), Rua Alfredo Allen 208, 4200-135 Porto, Portugal.
AD  - Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua 
      Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
AD  - Toxicology Research Unit (TOXRUN), University Institute of Health Sciences, 
      Polytechnic and University Cooperative (CESPU), Rua Central de Gandra, 1317, 
      4585-116 Gandra, Portugal.
FAU - Vale, Nuno
AU  - Vale N
AUID- ORCID: 0000-0002-1283-1042
AD  - OncoPharma Research Group, Center for Health Technology and Services Research 
      (CINTESIS), Rua Doutor Placido da Costa, 4200-450 Porto, Portugal.
AD  - CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor 
      Hernani Monteiro, 4200-319 Porto, Portugal.
AD  - Department of Community Medicine, Health Information and Decision (MEDCIDS), 
      Faculty of Medicine, University of Porto, Rua Doutor Placido da Costa, 4200-450 
      Porto, Portugal.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221016
PL  - Switzerland
TA  - Biomolecules
JT  - Biomolecules
JID - 101596414
RN  - 0 (Antimalarials)
RN  - 0 (Ki-67 Antigen)
RN  - N3D6TG58NI (Thioridazine)
RN  - 60W3249T9M (Artesunate)
RN  - 0 (NF-kappa B)
RN  - S79426A41Z (Fluphenazine)
RN  - 1NHL2J4X8K (Benztropine)
RN  - QUC7NX6WMB (Sertraline)
RN  - 01K63SUP8D (Fluoxetine)
RN  - 0 (Poly(ADP-ribose) Polymerase Inhibitors)
RN  - 681HV46001 (Ribose)
RN  - 0 (Antineoplastic Agents)
RN  - 80168379AG (Doxorubicin)
RN  - P88XT4IS4D (Paclitaxel)
RN  - U3P01618RT (Fluorouracil)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 886U3H6UFF (Chloroquine)
RN  - 61D2G4IYVH (Adenosine Diphosphate)
SB  - IM
MH  - Humans
MH  - Female
MH  - MCF-7 Cells
MH  - *Antimalarials/pharmacology/therapeutic use
MH  - Ki-67 Antigen/metabolism
MH  - Containment of Biohazards
MH  - Thioridazine/pharmacology/therapeutic use
MH  - Artesunate/pharmacology/therapeutic use
MH  - NF-kappa B/metabolism
MH  - Fluphenazine/pharmacology/therapeutic use
MH  - Benztropine/pharmacology/therapeutic use
MH  - Sertraline/pharmacology/therapeutic use
MH  - Fluoxetine/pharmacology/therapeutic use
MH  - Michigan
MH  - Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
MH  - Ribose/pharmacology/therapeutic use
MH  - *Antineoplastic Agents/pharmacology/therapeutic use
MH  - *Breast Neoplasms/metabolism
MH  - Doxorubicin/pharmacology/therapeutic use
MH  - Paclitaxel/pharmacology
MH  - Fluorouracil/pharmacology/therapeutic use
MH  - *Colonic Neoplasms/drug therapy
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
MH  - Chloroquine/pharmacology
MH  - Adenosine Diphosphate
MH  - Drug Resistance, Neoplasm
MH  - Cell Line, Tumor
PMC - PMC9599492
OTO - NOTNLM
OT  - CNS drugs
OT  - PPT1
OT  - antimalarial drugs
OT  - cancer therapy
OT  - drug combination
OT  - drug repurposing
COIS- The authors declare no conflict of interest.
EDAT- 2022/10/28 06:00
MHDA- 2022/10/29 06:00
PMCR- 2022/10/16
CRDT- 2022/10/27 01:13
PHST- 2022/09/03 00:00 [received]
PHST- 2022/10/10 00:00 [revised]
PHST- 2022/10/12 00:00 [accepted]
PHST- 2022/10/27 01:13 [entrez]
PHST- 2022/10/28 06:00 [pubmed]
PHST- 2022/10/29 06:00 [medline]
PHST- 2022/10/16 00:00 [pmc-release]
AID - biom12101490 [pii]
AID - biomolecules-12-01490 [pii]
AID - 10.3390/biom12101490 [doi]
PST - epublish
SO  - Biomolecules. 2022 Oct 16;12(10):1490. doi: 10.3390/biom12101490.