Organotin derivatives of cholic acid induce apoptosis into breast cancer cells and interfere with mitochondrion; Synthesis, characterization and biological evaluation

M E K Stathopoulou; N Zoupanou; C N Banti; A P Douvalis; C Papachristodoulou; K D Marousis; G A Spyroulias; T Mavromoustakos; S K Hadjikakou

doi:10.1016/j.steroids.2021.108798

Organotin derivatives of cholic acid induce apoptosis into breast cancer cells and interfere with mitochondrion; Synthesis, characterization and biological evaluation

Steroids. 2021 Mar:167:108798. doi: 10.1016/j.steroids.2021.108798. Epub 2021 Jan 17.

Authors

M E K Stathopoulou¹, N Zoupanou², C N Banti³, A P Douvalis⁴, C Papachristodoulou⁵, K D Marousis⁶, G A Spyroulias⁶, T Mavromoustakos⁷, S K Hadjikakou⁸

Affiliations

¹ Inorganic Chemistry Laboratory, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece.
² Organic Chemistry Laboratory, Department of Chemistry, National and Kapodistrian University of Athens, Greece.
³ Inorganic Chemistry Laboratory, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece. Electronic address: [email protected].
⁴ Mössbauer Spectroscopy and Physics of Materials Laboratory, Department of Physics, University of Ioannina, Greece; University Research Center of Ioannina (URCI), Institute of Materials Science and Computing, Ioannina, Greece.
⁵ Department of Physics, University of Ioannina, Greece.
⁶ Department of Pharmacy, University of Patras, GR 26504 Patras, Greece.
⁷ Organic Chemistry Laboratory, Department of Chemistry, National and Kapodistrian University of Athens, Greece. Electronic address: [email protected].
⁸ Inorganic Chemistry Laboratory, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece; University Research Center of Ioannina (URCI), Institute of Materials Science and Computing, Ioannina, Greece. Electronic address: [email protected].

PMID: 33472044
DOI: 10.1016/j.steroids.2021.108798

Abstract

Organotin(IV) derivatives of cholic acid (CAH) with the formulae R₃Sn(CA) (R = Ph- (1), n-Bu- (2)) and R₂Sn(CA)₂ (R = Ph- (3), n-Bu- (4) and Me- (5)) were synthesized. The compounds were characterized in solid state by melting point, FT-IR, ¹¹⁹Sn Mössbauer, X-ray fluorescence (XRF) spectroscopy and in solution by ¹H NMR, UV-Vis spectral data and by Electrospray Ionisation Mass spectrometry (ESI-MS), High Resolution Mass spectrometry (HRMS), and atomic absorption analysis. The in vitro bioactivity of 1-5 against human breast adenocarcinoma cancer cells MCF-7 (positive to hormone receptors) and MDA-MB-231 (negative to hormone receptors) reveal that triorganotin derivatives 1-2 exhibit significantly stronger activity than the corresponding diorganotin ones. Compound 5 is inactive against both cell lines at the concentrations tested. Triorganotins 1-2 inhibit selectively MCF-7 than MDA-MB-231 cells, suggesting hormone mimetic behavior of them. Organotins 1-4 inhibit both cancerous cell lines, stronger than cisplatin which rise up to 55-fold against MCF-7 and 170-fold against MDA-MB-231. The in vitro toxicity of 1-4 was evaluated on normal human fetal lung fibroblast cells (MRC-5), while their genotoxicity in vitro by micronucleus assay (MN). Moreover, the in vivo toxicity of 1-4 was tested by Artemia salina assay and their in vivo genotoxicity with Allium cepa test. The mechanism of action of 1-4 against MCF-7 was clarified in vitro by the means of cell morphology studies, cell cycle arrest, Acridine Orange/Ethidium Bromide (AO/EB) Staining, mitochondrial membrane permeabilization test and by their binding affinity toward the calf thymus (CT) DNA.

Keywords: Apoptosis; Bile acids; Bioinorganic chemistry; Breast cancer; Mitochondrion; Organotins.

MeSH terms

Animals
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis* / drug effects
Breast Neoplasms* / drug therapy
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cell Line, Tumor
Cholic Acid* / chemistry
Cholic Acid* / pharmacology
Female
Humans
MCF-7 Cells
MDA-MB-231 Cells
Mitochondria* / drug effects
Mitochondria* / metabolism
Organotin Compounds* / chemical synthesis
Organotin Compounds* / chemistry
Organotin Compounds* / pharmacology

Substances

Antineoplastic Agents
Cholic Acid
Organotin Compounds