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2022: Proteomics and Transcriptomics Uncover the Molecular Targets of CBD and THCV in the Sensitization of Doxorubicin against DOX-resistant MDAMB 231 Xenografts

Mandip Singh Sachdeva
Florida A&M University

Co-authors: Nimma Ramesh1, Anil Kumar Kalvala1, Arvind Bagde1
1Florida A&M University

Purpose: To study the Chemosensitization effects of cannabidiol (CBD) and tetrahydrocannabivarin (THCV) in combination with doxorubicin (DOX) against triple negative breast cancers xenografts.

Methods: The chemo sensitization effect of CBD and THCV in combination with DOX was studied using xenotransplanted DOX resistant MDA-MB-231 cells. After subcutaneous injection of 2.5 million DOX resistant MDA-MB-231 cells in 100 μL matrigel, nude mice were randomized to one of six groups (Control, DOX alone, CBD alone, CBD+DOX, THCV alone and THCV+DOX). In the combination study, CBD (10 mg/kg, i.p.) and THCV (15 mg/kg, i.p.) were given one day before DOX (5 mg/kg, i.p.) to assess the chemo sensitization effect. The treatment was repeated twice a week for 3 weeks until the control group reached 6000 mm3. Using a vernier caliper, the tumor volumes were measured. The animals were euthanized and their blood and tumors collected for further study.

Results: CBD and THCV pre-treatment effectively increased DOX’s anticancer potentials, reducing tumor growth and development in mice bearing DOX resistant MDA-MB-231 tumors. Data from RNA sequencing and proteomics revealed that CBD and THCV regulate apoptosis, oxidative stress, and inflammation by targeting the PDL-1 pathway, AMPK pathway, histone proteins, sertonergic pathway, CB1 receptors, and P38-MAPKinase pathway, thereby enhancing the chemosensitization effects of DOX against MDA-MB-231 breast cancers. RT-PCR and westernblot analysis were used to validate the same expression genes and proteins found in RNA sequencing and proteomics. In addition, we discovered significant changes in histone acetylations when CBD/THCV was combined with DOX.

Conclusion: According to the results of RNA sequencing and proteomic studies, CBD and THCV appear to have a chemosensitization effect on DOX by reversing histone modifications and their downstream effectors.

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