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Article

Synergistic Anticancer Activity of Cannabinoids and Terpenes Against Triple-Negative Breast Cancer Resistance

by
Mounika Aare
1,
Jassy Mary Lazarte
1,
Aakash Nathani
1,
Breana Boirie
1,
Tamiel N. Turley
2,
John A. Copland III
2 and
Mandip Singh
1,*
1
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
2
Cancer Biology Department, Mayo Clinic, Jacksonville, FL 32224, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(6), 2730; https://doi.org/10.3390/ijms27062730
Submission received: 18 December 2025 / Revised: 3 February 2026 / Accepted: 11 March 2026 / Published: 17 March 2026
(This article belongs to the Section Molecular Oncology)
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Abstract

Triple-negative breast cancer (TNBC) remains highly aggressive and refractory to conventional treatments, underscoring the need for novel combination strategies. Here, we employed 2D and 3D in vitro models, transcriptomic profiling, and in vivo xenograft studies to evaluate the anticancer efficacy of cannabinoids combined with the terpene β-caryophyllene (BC) in resistant TNBC models. Among the tested cannabinoids, cannabichromene (CBC) exhibited the greatest potency, and its combination with BC at sub-toxic concentrations significantly reduced IC50 values, enhanced cytotoxicity in spheroids, and suppressed colony formation and migration. The combination treatment induced pronounced G1 cell cycle arrest and increased apoptotic cell death. Western blot analyses revealed downregulation of PARP, Survivin, mTOR, Vimentin, Glypican-5, and PD-L1, while RNA sequencing demonstrated suppression of proliferative and migratory signaling pathways alongside activation of apoptosis, autophagy, and ferroptosis-related pathways. In vivo, CBC + BC significantly inhibited tumor growth in MDA-MB-231 xenografts, outperforming single-agent treatments. Collectively, these findings demonstrate that BC synergistically enhances cannabinoid activity, yielding superior antiproliferative and anti-migratory effects, and highlight this combination as a promising therapeutic strategy for resistant TNBC.
Keywords: cannabichromene; β-caryophyllene; combination therapy; triple-negative breast cancer cannabichromene; β-caryophyllene; combination therapy; triple-negative breast cancer
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MDPI and ACS Style

Aare, M.; Lazarte, J.M.; Nathani, A.; Boirie, B.; Turley, T.N.; Copland, J.A., III; Singh, M. Synergistic Anticancer Activity of Cannabinoids and Terpenes Against Triple-Negative Breast Cancer Resistance. Int. J. Mol. Sci. 2026, 27, 2730. https://doi.org/10.3390/ijms27062730

AMA Style

Aare M, Lazarte JM, Nathani A, Boirie B, Turley TN, Copland JA III, Singh M. Synergistic Anticancer Activity of Cannabinoids and Terpenes Against Triple-Negative Breast Cancer Resistance. International Journal of Molecular Sciences. 2026; 27(6):2730. https://doi.org/10.3390/ijms27062730

Chicago/Turabian Style

Aare, Mounika, Jassy Mary Lazarte, Aakash Nathani, Breana Boirie, Tamiel N. Turley, John A. Copland, III, and Mandip Singh. 2026. "Synergistic Anticancer Activity of Cannabinoids and Terpenes Against Triple-Negative Breast Cancer Resistance" International Journal of Molecular Sciences 27, no. 6: 2730. https://doi.org/10.3390/ijms27062730

APA Style

Aare, M., Lazarte, J. M., Nathani, A., Boirie, B., Turley, T. N., Copland, J. A., III, & Singh, M. (2026). Synergistic Anticancer Activity of Cannabinoids and Terpenes Against Triple-Negative Breast Cancer Resistance. International Journal of Molecular Sciences, 27(6), 2730. https://doi.org/10.3390/ijms27062730

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