PMID- 34791996
OWN - NLM
STAT- MEDLINE
DCOM- 20220221
LR  - 20220221
IS  - 1875-5453 (Electronic)
IS  - 1389-2002 (Linking)
VI  - 22
IP  - 13
DP  - 2021
TI  - How Antimalarials and Antineoplastic Drugs can Interact in Combination Therapies: 
      A Perspective on the Role of PPT1 Enzyme.
PG  - 1009-1016
LID - 10.2174/1389200222666211118114057 [doi]
AB  - Antimalarial drugs from different classes have demonstrated anticancer effects in 
      different types of cancer cells, but their complete mode of action in cancer 
      remains unknown. Recently, several studies reported the important role of 
      palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme, as the molecular 
      target of chloroquine and its derivates in cancer. It was also found that PPT1 is 
      overexpressed in different types of cancer, such as breast, colon, etc. Our group 
      has found a synergistic interaction between antimalarial drugs, such as 
      mefloquine, artesunate and chloroquine and antineoplastic drugs in breast cancer 
      cells, but the mechanism of action was not determined. Here, we describe the 
      importance of autophagy and lysosomal inhibitors in tumorigenesis and hypothesize 
      that other antimalarial agents besides chloroquine could also interact with PPT1 
      and inhibit the mechanistic target of rapamycin (mTOR) signalling, an important 
      pathway in cancer progression. We believe that PPT1 inhibition results in changes 
      in the lysosomal metabolism that result in less accumulation of antineoplastic 
      drugs in lysosomes, which increases the bioavailability of the antineoplastic 
      agents. Taken together, these mechanisms help to explain the synergism of 
      antimalarial and antineoplastic agents in cancer cells.
CI  - Copyright(c) Bentham Science Publishers; For any queries, please email at 
      epub@benthamscience.net.
FAU - Duarte, Diana
AU  - Duarte D
AD  - OncoPharma Research Group, Center for Health Technology and Services Research 
      (CINTESIS), Rua Dr. Placido da Costa, 4200-450 Porto,Portugal.
FAU - Vale, Nuno
AU  - Vale N
AD  - OncoPharma Research Group, Center for Health Technology and Services Research 
      (CINTESIS), Rua Dr. Placido da Costa, 4200-450 Porto,Portugal.
LA  - eng
GR  - IF/00092/2014/CP1255/CT0004, UIDB/4255/2020, SFRH/BD/140734/2018/Fundacao para a 
      Ciencia e a Tecnologia (FCT) National Funds/
PT  - Journal Article
PL  - Netherlands
TA  - Curr Drug Metab
JT  - Current drug metabolism
JID - 100960533
RN  - 0 (Antimalarials)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Membrane Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (PPT1 protein, human)
SB  - IM
MH  - Antimalarials/*pharmacology
MH  - Antineoplastic Agents/*pharmacology
MH  - Autophagy/drug effects
MH  - Biological Availability
MH  - Carcinogenesis/drug effects/metabolism
MH  - Drug Interactions
MH  - Drug Synergism
MH  - Drug Therapy, Combination
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - *Lysosomes/drug effects/enzymology
MH  - Membrane Proteins/*metabolism
MH  - Molecular Targeted Therapy/methods
MH  - *Neoplasms/drug therapy/metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Thiolester Hydrolases/*metabolism
OTO - NOTNLM
OT  - PPT1
OT  - antimalarial drugs
OT  - antineoplastic drugs
OT  - autophagy
OT  - drug combination.
OT  - mTOR
EDAT- 2021/11/19 06:00
MHDA- 2022/02/22 06:00
CRDT- 2021/11/18 08:45
PHST- 2021/06/16 00:00 [received]
PHST- 2021/09/15 00:00 [revised]
PHST- 2021/10/21 00:00 [accepted]
PHST- 2021/11/19 06:00 [pubmed]
PHST- 2022/02/22 06:00 [medline]
PHST- 2021/11/18 08:45 [entrez]
AID - CDM-EPUB-118924 [pii]
AID - 10.2174/1389200222666211118114057 [doi]
PST - ppublish
SO  - Curr Drug Metab. 2021;22(13):1009-1016. doi: 10.2174/1389200222666211118114057.