Pharmacogenomics to Predict Tumor Therapy Response: A Focus on ATP-Binding Cassette Transporters and Cytochromes P450

Hlaváč, Viktor; Holý, Petr; Souček, Pavel

doi:10.3390/jpm10030108

Cited by 17 publications

(29 citation statements)

References 110 publications

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“…ABCC5 is also involved in the efflux of different anticancer drugs such as 6-MP, 6-TG, 5-FU, and their metabolites [14][15][16][17][18][19], and this efflux is often associated with drug resistance. Additionally, studies have shown that gene polymorphisms of ABC transporters An equal amount of cell lysate (20 μg of protein/lane) was analyzed using β-actin as the loading control (*p < 0.05, compared with non-MTA treatment group; #p < 0.05, compared with AdvCtrl group) influence protein expression and determine the efficacy of some anticancer agents [36,37], despite paradoxical results in some studies.…”

Section: Discussionmentioning

confidence: 99%

Human drug efflux transporter ABCC5 confers acquired resistance to pemetrexed in breast cancer

et al. 2021

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Aim Pemetrexed, a new generation antifolate drug, has been approved for the treatment of locally advanced or metastatic breast cancer. However, factors affecting its efficacy and resistance have not been fully elucidated yet. ATP-binding cassette (ABC) transporters are predictors of prognosis as well as of adverse effects of several xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and can contribute to the optimization of breast cancer treatment regimen. Methods First, we measured the expression levels of ABC transporter family members in cell lines. Subsequently, we assessed the potential role of ABC transporters in conferring resistance to pemetrexed in primary breast cancer cells isolated from 34 breast cancer patients and the role of ABCC5 in mediating pemetrexed transport and apoptotic pathways in MCF-7 cells. Finally, the influence of ABCC5 expression on the therapeutic effect of pemetrexed was evaluated in an in vivo xenograft mouse model of breast cancer. Results The expression levels of ABCC2, ABCC4, ABCC5, and ABCG2 significantly increased in the pan-resistant cell line, and the ABCC5 level in the MCF-7-ADR cell line was 5.21 times higher than that in the control group. ABCC5 expression was inversely correlated with pemetrexed sensitivity (IC50, r = 0.741; p < 0.001) in breast cancer cells derived from 34 patients. Furthermore, we found that the expression level of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cells, with IC50 values of 0.06 and 0.20 μg/mL in ABCC5 knockout and over-expression cells, respectively. In the in vivo study, we observed that ABCC5 affected the sensitivity of pemetrexed in breast tumor-bearing mice, and the tumor volume was much larger in the ABCC5-overexpressing group than in the control group when compared with their own initial volumes (2.7-fold vs. 1.3-fold). Conclusions Our results indicated that ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and it may serve as a target or biomarker for the optimization of pemetrexed regimen in breast cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Human drug efflux transporter ABCC5 confers acquired resistance to pemetrexed in breast cancer

et al. 2021

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“…ABCC5 has also been shown to be involved in the e ux of many different anticancer drugs, for instance, 6-MP, 6-TG, 5-FU and its metabolites [10-12, 24, 25, 29], and this e ux was often considered to be associated with drug resistance. In addition, plenty of studies presented that the gene polymorphisms of ABC transporters in uence the proteins expressions and nally determine the e cacy of some anticancer agents [36,37] despite some paradoxical results in these studies were shown.…”

Section: Discussionmentioning

confidence: 99%

Human Drug Efflux Transporter ABCC5 Confers Acquired Resistance to Pemetrexed in Breast Cancer

Chen

Wang

Gao

et al. 2021

Preprint

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AimPemetrexed, a new generation antifolate drug, is approved for the treatment for locally advanced or metastatic breast cancer, but factors affecting the efficacy and resistance of it have yet to be fully explicit. ATP-binding cassette (ABC) transporters have been reported as prognostic and adverse effects predictors of many xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and may contribute to treatment regimen optimization for breast cancer.MethodsFirstly, the expression of ABC transporters family members was measured in cell lines, thereafter examined the potential role of ABC transporter in conferring resistance to pemetrexed in primary cancer cell lines isolated from 34 breast cancer patients, and then the role of ABCC5 in mediating transport of pemetrexed and apoptosis pathway in MCF-7 cell line was assessed. Finally, the functions of ABCC5 on therapeutic effect of pemetrexed was evaluated in breast cancer bearing mice.ResultsThe expressions of ABCC2, ABCC4, ABCC5 and ABCG2 were significantly increased in pan-resistance cell line, and the ABCC5, the most obvious one, was 5.21 times higher than that of the control group. The expression of ABCC5 was inversely correlated with sensitivity (IC50) of pemetrexed (r = 0.741; p<0.001) in breast cancer cells from 34 patients. Furthermore, we found that the expression of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cell line, and the IC50 were 0.06 μg/ml and 0.20 μg/ml in ABCC5 knock-down and over-expression cells, respectively. In in vivo study, we found ABCC5 affected the sensitivity of pemetrexed in breast cancer bearing mice, and the tumor volume was much larger in ABCC5 over-expression group than that in control group (2.7 folds vs 1.3 folds).ConclusionsOur results indicated ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and may be a biomarker for regimen optimization of pemetrexed in breast cancer treatment.

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“…However, while this collection of evidence hints at a possible network of pathways connecting oxysterols to anti-cancer drugs via ABC transporters, the research is lacking in scope and detail and does not provide any concrete answers. Using and combining modern methods such as highthroughput RNA and DNA sequencing (transcriptomics and genomics, respectively), proteomics and metabolomics might be able to bring new light into the area of ABC transporters that have been studied for several decades, such as ABCB1, ABCC1, and ABCG2 (Robey et al, 2018), as well as the remaining 45 known human ABCs which have received little attention in comparison (Hlavac, Holy, & Soucek, 2020).…”

Section: Chemotherapymentioning

confidence: 99%

Oxysterols in cancer management: From therapy to biomarkers

Kloudova-Spalenkova

Holý

Souček

2020

British J Pharmacology

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Oxysterols are oxidized derivatives of cholesterol, both endogenous and exogenous.They have been implicated in numerous pathologies, including cancer. In addition to their roles in carcinogenesis, proliferation, migration, apoptosis, and multiple signalling pathways, they have been shown to modulate cancer therapy. They are known to affect therapy of hormonally positive breast cancer through modulating oestrogen receptor activity. Oxysterols have also been shown in various in vitro models to influence efficacy of chemotherapeutics, such as doxorubicin, vincristine, cisplatin, 5-fluorouracil, and others. Their effects on the immune system should also be considered in immunotherapy. Selective anti-cancer cytotoxic properties of some oxysterols make them candidates for new therapeutic molecules. Finally, differences in oxysterol levels in blood of cancer patients in different stages or versus healthy controls, and in tumour versus non-tumour tissues, show potential of oxysterols as biomarkers for cancer management and patient stratification for optimization of therapy.

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Pharmacogenomics to Predict Tumor Therapy Response: A Focus on ATP-Binding Cassette Transporters and Cytochromes P450

Cited by 17 publications

References 110 publications

Human drug efflux transporter ABCC5 confers acquired resistance to pemetrexed in breast cancer

Human drug efflux transporter ABCC5 confers acquired resistance to pemetrexed in breast cancer

Human Drug Efflux Transporter ABCC5 Confers Acquired Resistance to Pemetrexed in Breast Cancer

Oxysterols in cancer management: From therapy to biomarkers

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