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Modifying gap junction communication in cancer therapy.
- Source :
-
Current research in translational medicine [Curr Res Transl Med] 2021 Jan; Vol. 69 (1), pp. 103268. Date of Electronic Publication: 2020 Oct 15. - Publication Year :
- 2021
-
Abstract
- Aim: Drug delivery is crucial for therapeutic efficacy and gap junction communication channels (GJIC) facilitate movement within the tumour. Pro-drug activation, a modality of cancer therapy leads to Ganciclovir triphosphate (GCV-TP) incorporation into newly synthesized DNA resulting in cell death. The objective was to enhance, with Histone deacetylase inhibitors (HDACi) and All Trans Retinoic Acid (ATRA), GJIC, crucial for drug delivery, and with combination, abrogate the observed detrimental effect of Dexamethasone (DXM).<br />Methods: Cell lines (NT8E, and HeLa) were pre-treated with Valproic Acid (VPA) (1 mM), 4 Phenyl Butyrate (4PB) (2 mM), ATRA (10 μM) and Dexamethasone (1 μM). Protein quantitated with the Bicinchoninic (BCA) assay for cell lysates, membrane and soluble fractions was assessed with Western blotting for Connexins (43, 26 and 32) and E-Cadherin. A qRT-PCR was done for CX 43-GJA1, CX 26-GJB2, CX 32-GJB1 and E-Cadherin, and normalized with Glyceraldehyde Phosphate dehydrogenase (GAPDH). Further, localization of Connexins (CX) and E-Cadherin, GJIC competence, pre-clinical in-vitro studies and the mechanism of cell death were evaluated.<br />Results: There was no toxicity or change in growth patterns observed with the drugs. In both the cell lines CX 43 localized to the membrane whereas CX 32 and CX 26 were present but not membrane bound. E-Cadherin was present on the membrane in NT8E and completely absent in HeLa cells. Effects of HDACi, DXM and ATRA were seen on the expression of Connexins and E-Cadherin in both the cell lines. NT8E and HeLa cell lines showed enhanced GJIC with 4PB [30 %], VPA [36 %] and ATRA [54 %] with a 60 % increase in cytotoxicity and an abrogation of Dexamethasone inhibition on combination with VPA or ATRA.<br />Conclusion: An enhancement of GJIC function by HDACi and ATRA increased cytotoxicity and could be effective in the presence of Dexamethasone, when combined with ATRA or VPA.<br /> (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Antineoplastic Agents administration & dosage
Apoptosis drug effects
Cadherins drug effects
Cadherins genetics
Cadherins metabolism
Cell Communication drug effects
Cell Communication physiology
Cell Line, Tumor
Cell Membrane drug effects
Connexins drug effects
Connexins genetics
Connexins metabolism
Dexamethasone administration & dosage
Dexamethasone pharmacology
Ganciclovir administration & dosage
Ganciclovir analogs & derivatives
Ganciclovir pharmacology
Gap Junctions physiology
Gene Expression Regulation, Neoplastic drug effects
HeLa Cells
Histone Deacetylase Inhibitors administration & dosage
Histone Deacetylase Inhibitors pharmacology
Humans
Neoplasms genetics
Neoplasms pathology
Tretinoin administration & dosage
Tretinoin pharmacology
Valproic Acid administration & dosage
Valproic Acid pharmacology
Antineoplastic Agents pharmacology
Gap Junctions drug effects
Molecular Targeted Therapy methods
Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 2452-3186
- Volume :
- 69
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Current research in translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 33069641
- Full Text :
- https://doi.org/10.1016/j.retram.2020.09.002