Lovastatin enhances chemosensitivity of paclitaxel-resistant prostate cancer cells through inhibition of CYP2C8.
Cell Line, Tumor
Cytochrome P-450 CYP2C8
/ genetics
Cytochrome P-450 CYP2C8 Inhibitors
/ pharmacology
Drug Resistance, Neoplasm
/ drug effects
Drug Synergism
Gene Expression Regulation, Enzymologic
/ drug effects
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Kaplan-Meier Estimate
Lovastatin
/ pharmacology
Male
Models, Biological
Paclitaxel
/ pharmacology
Prognosis
Prostatic Neoplasms
/ enzymology
CYP2C8
Drug sensitivity
Lovastatin
Paclitaxel
Prostate cancer
Journal
Biochemical and biophysical research communications
ISSN: 1090-2104
Titre abrégé: Biochem Biophys Res Commun
Pays: United States
ID NLM: 0372516
Informations de publication
Date de publication:
22 01 2022
22 01 2022
Historique:
received:
23
11
2021
revised:
27
11
2021
accepted:
02
12
2021
pubmed:
14
12
2021
medline:
9
2
2022
entrez:
13
12
2021
Statut:
ppublish
Résumé
Chemotherapy is the mainstay of treatment for prostate cancer, with paclitaxel being commonly used for hormone-resistant prostate cancer. However, drug resistance often develops and leads to treatment failure in a variety of prostate cancer patients. Therefore, it is necessary to enhance the sensitivity of prostate cancer to chemotherapy. Lovastatin (LV) is a natural compound extracted from Monascus-fermented foods and is an inhibitor of HMG-CoA reductase (HMGCR), which has been approved by the FDA for hyperlipidemia treatment. We have previously found that LV could inhibit the proliferation of refractory cancer cells. Up to now, the effect of LV on chemosensitization and the mechanisms involved have not been evaluated in drug-resistant prostate cancer. In this study, we used prostate cancer cell line PC3 and its paclitaxel-resistant counterpart PC3-TxR as the cell model. Alamar Blue cell viability assay showed that LV and paclitaxel each conferred concentration-dependent inhibition of PC3-TxR cells. When paclitaxel was combined with LV, the proliferation of PC3-TxR cells was synergistically inhibited, as demonstrated by combination index <1. Moreover, colony formation decreased while apoptosis increased in paclitaxel plus LV group compared with paclitaxel alone group. Quantitative RT-PCR showed that the combination of paclitaxel and LV could significantly reduce the expression of CYP2C8, an important drug-metabolizing enzyme. Bioinformatics analysis from the TCGA database showed that CYP2C8 expression was negatively correlated with progression-free survival (PFS) in prostate cancer patients. Our results suggest that LV might increase the sensitivity of resistant prostate cancer cells to paclitaxel through inhibition of CYP2C8 and could be utilized as a chemosensitizer for paclitaxel-resistant prostate cancer cells.
Identifiants
pubmed: 34896780
pii: S0006-291X(21)01642-9
doi: 10.1016/j.bbrc.2021.12.007
pii:
doi:
Substances chimiques
Cytochrome P-450 CYP2C8 Inhibitors
0
Lovastatin
9LHU78OQFD
Cytochrome P-450 CYP2C8
EC 1.14.14.1
Paclitaxel
P88XT4IS4D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
85-91Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare no conflicts of interest.