Anticancer and chemosensitization effects of cannabidiol in 2D and 3D cultures of TNBC: involvement of GADD45α, integrin-α5, -β5, -β1, and autophagy

To date, promising therapy for triple negative breast cancer (TNBC) remains a serious concern clinically because of poor prognosis, resistance, and recurrence. Herein, anti-cancer potential of synthetic cannabidiol (CBD; Purisys, GA; GMP grade) was explored either alone or as a chemosensitizer follo...

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Published inDrug delivery and translational research Vol. 12; no. 11; pp. 2762 - 2777
Main Authors Surapaneni, Sunil Kumar, Patel, Nilkumar, Sun, Li, Kommineni, Nagavendra, Kalvala, Anil Kumar, Gebeyehu, Aragaw, Arthur, Peggy, Duke, Leanne C., Nimma, Ramesh, G Meckes, David, Singh, Mandip
Format Journal Article
LanguageEnglish
Published New York Springer US 01.11.2022
Subjects
Apoptosis
Autophagy
Beclin-1 - metabolism
Beclin-1 - pharmacology
Biomedical and Life Sciences
Biomedicine
Cannabidiol - pharmacology
Caspase 9 - metabolism
Caspase 9 - pharmacology
Cell Line, Tumor
Cell Proliferation
Doxorubicin - pharmacology
Fibronectins
Humans
Hydrogels
Integrin alpha5 - metabolism
Integrin alpha5 - pharmacology
Original Article
Pharmaceutical Sciences/Technology
Triple Negative Breast Neoplasms - drug therapy
Triple Negative Breast Neoplasms - metabolism
Vimentin - metabolism
Vimentin - pharmacology
Cannabidiol
TNBC
GADD45α
Doxorubicin
Autophagy
Integrins
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Summary:To date, promising therapy for triple negative breast cancer (TNBC) remains a serious concern clinically because of poor prognosis, resistance, and recurrence. Herein, anti-cancer potential of synthetic cannabidiol (CBD; Purisys, GA; GMP grade) was explored either alone or as a chemosensitizer followed by post-treatment with doxorubicin (DOX) in TNBC (i.e., MDA-MB-231 and MDA-MB-468) cells. In comparison to 2D cultures, CBD showed greater IC 50 values in 3D (LDP2 hydrogel based) cultures of MDA-MB-231 (6.26-fold higher) and MDA-MB-468 (10.22-fold higher) cells. Next-generation RNA sequencing revealed GADD45A , GADD45G , FASN , LOX , and integrin (i.e., -α5, -β5) genes to be novelly altered by CBD in MDA-MB-231 cells. CIM-16 plate-based migration assay and western blotting disclosed that CBD induces anti-migratory effects in TNBC cells by decreasing fibronectin, vimentin, and integrins-α5, -β5, and -β1. Western blotting, RT-qPCR, and immunocytochemistry revealed that CBD inhibited autophagy (decreased Beclin1, and ATG-5, -7, and -16) of TNBC cells. CBD pre-treatment increased DOX sensitivity in TNBC cells. CBD pre-treatment accompanied by DOX treatment decreased LOX and integrin-α5, and increased caspase 9 protein respectively in MDA-MB-468 cells. Graphical abstract
Bibliography:Author contributions S.K.S. designed and conducted all cell culture studies, flow cytometry, RT-qPCR, western blotting, and RNA seq data analysis. N.P. performed all the western blot studies. L.S. performed the RNA seq studies and also data analysis. N.K. conducted in-vitro cytotoxicity studies. A.K.K. performed confocal microscopy and flow cytometry studies. A.G. conducted the 3D culture cytotoxicity studies. L.C.D. conducted the cell migration studies. P.A. conducted the in-vitro cytotoxicity studies. R.N. performed western blotting. D.G.M provided lab facilities for conducting cell migration and RNA seq studies. S.K.S. and N.P. wrote the manuscript. M.S. majorly contributed in designing and supervision of experiments (i.e., in-vitro and in vivo), and also approved the manuscript final draft. Manuscript had been reviewed by all the authors.
ISSN:2190-393X
2190-3948
DOI:10.1007/s13346-022-01137-2