Drug metabolizing enzymes-associated chemo resistance and strategies to overcome it

Verma, Himanshu; Bahia, Malkeet Singh; Choudhary, Shalki; Singh, Pankaj Kumar; Silakari, Om

doi:10.1080/03602532.2019.1632886

Cited by 39 publications

(25 citation statements)

References 153 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides the CYPs, we focused also on UGTs. The association of UGTs with resistance to several drug classes has been shown in human therapy [32,33]. Recently, UGTs have been considered key players in insecticide resistance [34].…”

Section: Discussionmentioning

confidence: 99%

Sub-lethal doses of albendazole induce drug metabolizing enzymes and increase albendazole deactivation in Haemonchus contortus adults

Kellerová¹,

Stuchlíková²,

Matoušková³

et al. 2020

Vet Res

View full text Add to dashboard Cite

The efficacy of anthelmintic therapy of farm animals rapidly decreases due to drug resistance development in helminths. In resistant isolates, the increased expression and activity of drug-metabolizing enzymes (DMEs), e.g. cytochromes P450 (CYPs), UDP-glycosyltransferases (UGTs) and P-glycoprotein transporters (P-gps), in comparison to sensitive isolates have been described. However, the mechanisms and circumstances of DMEs induction are not well known. Therefore, the present study was designed to find the changes in expression of CYPs, UGTs and P-gps in adult parasitic nematodes Haemonchus contortus exposed to sub-lethal doses of the benzimidazole anthelmintic drug albendazole (ABZ) and its active metabolite ABZ-sulfoxide (ABZSO). In addition, the effect of ABZ at sub-lethal doses on the ability to deactivate ABZ during consequent treatment was studied. The results showed that contact of H. contortus adults with sub-lethal doses of ABZ and ABZSO led to a significant induction of several DMEs, particularly cyp-2, cyp-3

show abstract

Section: Discussionmentioning

confidence: 99%

Sub-lethal doses of albendazole induce drug metabolizing enzymes and increase albendazole deactivation in Haemonchus contortus adults

Kellerová¹,

Stuchlíková²,

Matoušková³

et al. 2020

Vet Res

View full text Add to dashboard Cite

show abstract

“…Of note, it was shown that the expression of CYPs in tumor cells was usually aberrant, compared with adjacent normal tissues [ 23 ]. The low expression and activity of CYPs, partly owing to distinctive metabolic reprogramming and living conditions, may reduce the activation of antitumor agents in tumor cells, whilst the overexpression of CYPs in tumor cells may rapidly devitalize tumor agent substrates, which may be associated with treatment resistance and cause subsequent tumor relapse and poor prognosis [ 24 , 25 ]. Accordingly, CYPs have been considered as targets and indicators for antitumor therapy because of their aberrant expression in tumor cells [ 26 , 27 ].…”

Section: Human Cypsmentioning

confidence: 99%

Cytochrome P450 Enzymes and Drug Metabolism in Humans

Zhao

Ma²,

et al. 2021

IJMS

252

147

View full text Add to dashboard Cite

Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1–3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.

show abstract

“…Lower drug uptake and enhanced drug efflux, which lower intracellular drug accumulation, are well-studied mechanisms to restrain chemoresistance. Moreover, increased drug metabolism has emerged as a potential mechanism to decrease intracellular drug accumulation that confers chemoresistance 55 . Studies on DOX metabolism have shown that reduced DOX within cells due to drug metabolism significantly affects the treatment outcome of this drug 40 .…”

Section: Discussionmentioning

confidence: 99%

piR-39980 mediates doxorubicin resistance in fibrosarcoma by regulating drug accumulation and DNA repair

2021

View full text Add to dashboard Cite

Resistance to doxorubicin (DOX) is an obstacle to successful sarcoma treatment and a cause of tumor relapse, with the underlying molecular mechanism still unknown. PIWI-interacting RNAs (piRNAs) have been shown to enhance patient outcomes in cancers. However, there are few or no reports on piRNAs affecting chemotherapy in cancers, including fibrosarcoma. The current study aims to investigate the relationship between piR-39980 and DOX resistance and the underlying mechanisms. We reveal that piR-39980 is less expressed in DOX-resistant HT1080 (HT1080/DOX) fibrosarcoma cells. Our results show that inhibition of piR-39980 in parental HT1080 cells induces DOX resistance by attenuating intracellular DOX accumulation, DOX-induced apoptosis, and anti-proliferative effects. Its overexpression in HT1080/DOX cells, on the other hand, increases DOX sensitivity by promoting intracellular DOX accumulation, DNA damage, and apoptosis. The dual-luciferase reporter assay indicates that piR-39980 negatively regulates RRM2 and CYP1A2 via direct binding to their 3′UTRs. Furthermore, overexpressing RRM2 induces DOX resistance of HT1080 cells by rescuing DOX-induced DNA damage by promoting DNA repair, whereas CYP1A2 confers resistance by decreasing intracellular DOX accumulation, which piR-39980 restores. This study reveals that piR-39980 could reduce fibrosarcoma resistance to DOX by modulating RRM2 and CYP1A2, implying that piRNA can be used in combination with DOX.

show abstract

Drug metabolizing enzymes-associated chemo resistance and strategies to overcome it

Cited by 39 publications

References 153 publications

Sub-lethal doses of albendazole induce drug metabolizing enzymes and increase albendazole deactivation in Haemonchus contortus adults

Sub-lethal doses of albendazole induce drug metabolizing enzymes and increase albendazole deactivation in Haemonchus contortus adults

Cytochrome P450 Enzymes and Drug Metabolism in Humans

piR-39980 mediates doxorubicin resistance in fibrosarcoma by regulating drug accumulation and DNA repair

Contact Info

Product

Resources

About