Overexpression of cytochrome P450 2A6 in adrenocortical carcinoma

Murtha, Timothy D.; Brown, Taylor C.; Rubinstein, Jill C.; Haglund, Felix; Juhlin, C. Christofer; Korah, Reju; Carling, Tobias

doi:10.1016/j.surg.2016.11.036

Cited by 10 publications

(8 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…67 The expression of protein kinase cAMP-dependent type I regulatory subunit α, which is involved in the activation of steroidogenesis, was also reduced following 24 hours of treatment with mitotane. 53 This confirms that mitotane binds specifically to CYP11A1.…”

Section: Inhibition Of Steroidogenesissupporting

confidence: 57%

“…Interestingly, incubation with translocator protein inhibitor in combination with mitotane significantly potentiated the antitumour and antisecretory actions of mitotane in H295R cells 67 . The expression of protein kinase cAMP‐dependent type I regulatory subunit α, which is involved in the activation of steroidogenesis, was also reduced following 24 hours of treatment with mitotane 53 . This confirms that mitotane binds specifically to CYP11A1.…”

Section: Pharmacological Aspectsmentioning

confidence: 59%

“…Other CYPs are also related to the effects of mitotane. Recently, Murtha and colleagues demonstrated that silencing of CYP2A6 mRNA in H295R cells promoted higher sensitivity of this cell line to the effects of mitotane 53 . This enzyme is a known metabolizer of some xenobiotics; however, the exact function of CYP2A6 in ACC is still unclear.…”

Section: Pharmacological Aspectsmentioning

confidence: 99%

“…Recently, Murtha and colleagues demonstrated that silencing of CYP2A6 mRNA in H295R cells promoted higher sensitivity of this cell line to the effects of mitotane. 53 This enzyme is a known metabolizer of some…”

Section: Metabolismmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacological profile and effects of mitotane in adrenocortical carcinoma

Corso

Acco

Bach

et al. 2021

Brit J Clinical Pharma

View full text Add to dashboard Cite

Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour tissues; it induces cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids, which are involved in the pathogenesis of ACC. However, high doses of mitotane are usually necessary to reach the therapeutic plasma concentration, which may result in several adverse effects. This suggests that important pharmacological processes, such as first pass metabolism, tissue accumulation and extensive time for drug elimination, are associated with mitotane administration. Few studies have reported the pharmacological aspects and therapeutic effects of mitotane. Therefore, the aim of this review was to summarize the chemistry, pharmacokinetics and pharmacodynamics, and therapeutic and toxic effects of mitotane. This review also discusses new perspectives of mitotane formulation that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects.

show abstract

Section: Inhibition Of Steroidogenesissupporting

confidence: 57%

Section: Pharmacological Aspectsmentioning

confidence: 59%

Section: Pharmacological Aspectsmentioning

confidence: 99%

Section: Metabolismmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacological profile and effects of mitotane in adrenocortical carcinoma

Corso

Acco

Bach

et al. 2021

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…We assumed that a similar mechanism could be the case for the CYP2B6 phenotypes. While no one demonstrated until now that this cytochrome is overexpressed in ACC, there is however evidence of gene amplifications associated with ACC [30].…”

Section: Discussionmentioning

confidence: 97%

Effects of Germline CYP2W16 and CYP2B66 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study

Altieri

Sbiera

Herterich

et al. 2020

Cancers

View full text Add to dashboard Cite

Mitotane is the only approved drug for advanced adrenocortical carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentrations and clinical response. Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers. A multicenter cohort study including 182 ACC patients (F/M = 121/61) treated with mitotane monotherapy after radical resection (group A, n = 103) or in not completely resectable, recurrent or advanced disease (group B, n = 79) was performed. CYP2W1*2, CYP2W1*6, CYP2B6*6 and CYP2B6 rs4803419 were genotyped in germline DNA. Mitotane blood levels were measured regularly. Response to therapy was evaluated as time to progression (TTP) and disease control rate (DCR). Among investigated SNPs, CYP2W1*6 and CYP2B6*6 correlated with mitotane treatment only in group B. Patients with CYP2W1*6 (n = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2% vs 51.7%, p = 0.051) and experienced shorter TTP (HR = 2.10, p = 0.019) and lower DCR (chi-square = 6.948, p = 0.008). By contrast, 55% of patients with CYP2B6*6 vs. 28.2% WT (p = 0.016) achieved therapeutic range. Combined, a higher rate of patients with CYP2W1*6WT+CYP2B6*6 (60.6%) achieved mitotane therapeutic range (p = 0.034). In not completely resectable, recurrent or advanced ACC, CYP2W1*6 SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas CYP2B6*6 correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.

show abstract

Retracted: Upregulation of microRNA‐140‐3p inhibits epithelial‐mesenchymal transition, invasion, and metastasis of hepatocellular carcinoma through inactivation of the MAPK signaling pathway by targeting GRN

Zhang

Men

Ding

2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

Invasion and metastasis in hepatocellular carcinoma (HCC) results in poor prognosis. Human intervention in these pathological processes may benefit the treatment of HCC. The aim of the present study is to elucidate the mechanism of miR‐140‐3p affecting epithelial‐mesenchymal transition (EMT), invasion, and metastasis in HCC. Microarray analysis was performed for differentially expressed genes screening. The target relationship between miR‐140‐3p and GRN was analyzed. Small interfering RNA (siRNA) against granulin (GRN) was synthesized. EMT markers were detected, and invasion and migration were evaluated in HCC cells introduced with a miR‐140‐3p inhibitor or mimic, or siRNA against GRN. A mechanistic investigation was conducted for the determination of mitogen‐activated protein kinase (MAPK) signaling pathway‐related genes and EMT markers (E‐cadherin, N‐cadherin, and Vimentin). GRN was highlighted as an upregulated gene in HCC. GRN was a target gene of miR‐140‐3p. Elevation of miR‐140‐3p or inhibition of GRN restrained the EMT process and suppressed the HCC cell migration and invasion. HCC cells treated with the miR‐140‐3p mimic or siRNA‐GRN exhibited decreased GRN expression and downregulated the expressions of the MAPK signaling pathway‐related genes, N‐cadherin, and Vimentin but upregulated the expression of E‐cadherin. GRN silencing can reverse the activation of the MAPK signaling pathway and induction of EMT mediated by miR‐140‐3p inhibition. Taken together, the results show that miR‐140‐3p confers suppression of the MAPK signaling pathway by targeting GRN, thus inhibiting EMT, invasion, and metastasis in HCC.

show abstract

Overexpression of cytochrome P450 2A6 in adrenocortical carcinoma

Abstract: Frequent upregulation in adrenocortical carcinomas and the reversal of chemoresistance in adrenocortical carcinoma cells via enforced silencing suggest a role for CYP2A6 in adrenocortical malignancy.

Cited by 10 publications

References 24 publications

Pharmacological profile and effects of mitotane in adrenocortical carcinoma

Pharmacological profile and effects of mitotane in adrenocortical carcinoma

Effects of Germline CYP2W16 and CYP2B66 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study

Retracted: Upregulation of microRNA‐140‐3p inhibits epithelial‐mesenchymal transition, invasion, and metastasis of hepatocellular carcinoma through inactivation of the MAPK signaling pathway by targeting GRN

Contact Info

Product

Resources

About

Overexpression of cytochrome P450 2A6 in adrenocortical carcinoma

Abstract: Frequent upregulation in adrenocortical carcinomas and the reversal of chemoresistance in adrenocortical carcinoma cells via enforced silencing suggest a role for CYP2A6 in adrenocortical malignancy.

Cited by 10 publications

References 24 publications

Pharmacological profile and effects of mitotane in adrenocortical carcinoma

Pharmacological profile and effects of mitotane in adrenocortical carcinoma

Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study

Retracted: Upregulation of microRNA‐140‐3p inhibits epithelial‐mesenchymal transition, invasion, and metastasis of hepatocellular carcinoma through inactivation of the MAPK signaling pathway by targeting GRN

Contact Info

Product

Resources

About

Effects of Germline CYP2W16 and CYP2B66 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study