Albumin/Mitotane Interaction Affects Drug Activity in Adrenocortical Carcinoma Cells: Smoke and Mirrors on Mitotane Effect with Possible Implications for Patients' Management.
H295R cell line
adrenocortical carcinoma
albumin
drug resistance
human serum
mitotane
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
24 Nov 2023
24 Nov 2023
Historique:
received:
02
11
2023
revised:
22
11
2023
accepted:
22
11
2023
medline:
9
12
2023
pubmed:
9
12
2023
entrez:
9
12
2023
Statut:
epublish
Résumé
Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). Although it has been used for many years, its mechanism of action remains elusive. H295R cells are, in ACC, an essential tool to evaluate drug mechanisms, although they often lead to conflicting results. Using different in vitro biomolecular technologies and biochemical/biophysical experiments, we evaluated how the presence of "confounding factors" in culture media and patient sera could reduce the pharmacological effect of mitotane and its metabolites. We discovered that albumin, the most abundant protein in the blood, was able to bind mitotane. This interaction altered the effect of the drug by blocking its biological activity. This blocking effect was independent of the albumin source or methodology used and altered the assessment of drug sensitivity of the cell lines. In conclusion, we have for the first time demonstrated that albumin does not only act as an inert drug carrier when mitotane or its metabolites are present. Indeed, our experiments clearly indicated that both albumin and human serum were able to suppress the pharmacological effect of mitotane in vitro. These experiments could represent a first step towards the individualization of mitotane treatment in this rare tumor.
Sections du résumé
BACKGROUND
BACKGROUND
Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). Although it has been used for many years, its mechanism of action remains elusive. H295R cells are, in ACC, an essential tool to evaluate drug mechanisms, although they often lead to conflicting results.
METHODS
METHODS
Using different in vitro biomolecular technologies and biochemical/biophysical experiments, we evaluated how the presence of "confounding factors" in culture media and patient sera could reduce the pharmacological effect of mitotane and its metabolites.
RESULTS
RESULTS
We discovered that albumin, the most abundant protein in the blood, was able to bind mitotane. This interaction altered the effect of the drug by blocking its biological activity. This blocking effect was independent of the albumin source or methodology used and altered the assessment of drug sensitivity of the cell lines.
CONCLUSIONS
CONCLUSIONS
In conclusion, we have for the first time demonstrated that albumin does not only act as an inert drug carrier when mitotane or its metabolites are present. Indeed, our experiments clearly indicated that both albumin and human serum were able to suppress the pharmacological effect of mitotane in vitro. These experiments could represent a first step towards the individualization of mitotane treatment in this rare tumor.
Identifiants
pubmed: 38069023
pii: ijms242316701
doi: 10.3390/ijms242316701
pmc: PMC10706292
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Italian Association for Cancer Research
ID : IG2019-23069
Références
Int J Biol Macromol. 2020 Nov 1;162:1484-1493
pubmed: 32781122
Int J Oncol. 2019 Jun;54(6):2149-2156
pubmed: 30942448
Ann Clin Biochem. 2016 Jan;53(Pt 1):106-11
pubmed: 26071488
Br J Clin Pharmacol. 2021 Jul;87(7):2698-2710
pubmed: 33382119
Biotechnol Appl Biochem. 2018 Jan;65(1):46-53
pubmed: 28926141
Horm Cancer. 2014 Oct;5(5):312-23
pubmed: 25026941
Biomed Res Int. 2018 Jun 04;2018:9362108
pubmed: 29967789
Exp Clin Endocrinol Diabetes. 2020 Oct;128(10):672-680
pubmed: 32349159
Gene. 2016 Nov 15;593(1):91-99
pubmed: 27523475
Int J Mol Sci. 2022 Mar 25;23(7):
pubmed: 35408976
J Chem Inf Model. 2021 Aug 23;61(8):3891-3898
pubmed: 34278794
J Vis Exp. 2017 Mar 4;(121):
pubmed: 28287565
Mol Immunol. 2012 Oct;52(3-4):174-82
pubmed: 22677715
J Phys Chem B. 2014 Jul 3;118(26):7267-76
pubmed: 24915234
N Engl J Med. 2007 Jun 7;356(23):2415-8
pubmed: 17554125
Int J Biol Macromol. 1990 Aug;12(4):263-8
pubmed: 2096908
PLoS One. 2013 Aug 09;8(8):e71422
pubmed: 23951159
J Clin Endocrinol Metab. 2015 Aug;100(8):2890-8
pubmed: 26120791
Eur J Endocrinol. 2022 Jul 19;187(3):R27-R40
pubmed: 35695575
Endocr Relat Cancer. 2020 Jun;27(6):361-373
pubmed: 32276262
J Steroid Biochem. 1973 Nov;4(6):585-91
pubmed: 4789318
Cell Death Dis. 2020 Mar 17;11(3):192
pubmed: 32184394
Endocr Connect. 2020 Feb;9(2):122-134
pubmed: 31910152
Antioxidants (Basel). 2021 Mar 08;10(3):
pubmed: 33800425
J Comput Chem. 2010 Jan 30;31(2):455-61
pubmed: 19499576
Proteins. 2002 May 15;47(3):393-402
pubmed: 11948792
Endocrinology. 2015 Nov;156(11):3895-908
pubmed: 26305886
Arch Surg. 1982 Sep;117(9):1142-6
pubmed: 7115060
Arch Biochem Biophys. 2013 Mar;531(1-2):14-23
pubmed: 23098780
Pharmaceuticals (Basel). 2022 Nov 29;15(12):
pubmed: 36558937
Eur J Drug Metab Pharmacokinet. 2021 Sep;46(5):575-593
pubmed: 34287806
Phys Biol. 2009 Feb 10;6(1):015001
pubmed: 19208936
Arch Pathol (Chic). 1949 Nov;48(5):387-94
pubmed: 18143915
Int J Biol Macromol. 2016 Nov;92:1049-1056
pubmed: 27506123
Biomolecules. 2020 Mar 06;10(3):
pubmed: 32155758
Cancers (Basel). 2021 Oct 20;13(21):
pubmed: 34771418
Mol Cell Endocrinol. 2014 Jan 25;382(1):1-7
pubmed: 24018612
N Engl J Med. 2012 Jun 7;366(23):2189-97
pubmed: 22551107