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

Abstract

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 IC50 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.

• Authors: Sunil Kumar Surapaneni, Nilkumar Patel, Li Sun, Nagavendra Kommineni, Anil Kumar Kalvala, Aragaw Gebeyehu, Peggy Arthur, Leanne C Duke, Ramesh Nimma, David G Meckes Jr, Mandip Singh
• Journal: Drug delivery and translational research (Drug Deliv Transl Res) Vol. 12 Issue 11 Pg. 2762-2777 (11 2022) ISSN: 2190-3948 [Electronic] United States
• PMID: 35217991 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Chemical References

• Beclin-1
• Fibronectins
• Hydrogels
• Integrin alpha5
• Vimentin
• Cannabidiol
• Doxorubicin
• Caspase 9

Topics

• Apoptosis
• Autophagy
• Beclin-1 (metabolism, pharmacology)
• Cannabidiol (pharmacology)
• Caspase 9 (metabolism, pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Doxorubicin (pharmacology)
• Fibronectins
• Humans
• Hydrogels
• Integrin alpha5 (metabolism, pharmacology)
• Triple Negative Breast Neoplasms (drug therapy, metabolism)
• Vimentin (metabolism, pharmacology)