Network pharmacology-based therapeutic intervention of Mentha arvensis targeting cancer and doxorubicin-induced cardiotoxicity.

Abstract

Background: Doxorubicin (Dox) is a widely used chemotherapeutic agent effective against hematological malignancies and solid tumors, including leukemia, breast and bladder cancers, lymphomas, and Kaposi's sarcoma. Despite its clinical efficacy, the therapeutic application of Dox is severely limited by dose-dependent cardiotoxicity, manifesting as both acute and chronic Doxorubicin-induced cardiotoxicity (DIC). Dexrazoxane (Dexa) remains the only FDA-approved cardioprotective agent available; however, it compromises the anti-cancer activity of Dox and poses risks such as secondary malignancies, particularly in pediatric patients. This unmet clinical challenge underscores the urgent need for safer and more effective therapeutic strategies that preserve the anticancer potency of Dox while preventing or minimizing doxorubicin-induced cardiotoxicity.

Methods: A network pharmacology-based strategy was adopted to screen phytochemicals of Mentha arvensis. Compounds were filtered based on plasma bound fraction and volume of distribution by Deep-PK. Protein-protein interaction (PPI) networks and hub gene analyses were performed to determine key targets common to DIC and cancer. Molecular docking studies evaluated the interactions of phytochemicals alone and in combination with Dexa against critical targets implicated in both cancer and cardiotoxicity.

Results: A total of 39 phytochemicals were screened including Methyl acetate, p-Menthan-3-one, trans-Linalool, Piperitone, Octyl acetate, Camphor, Dihydrocarveol, p-Menthan-3-one, Furfural, Menthol, 3-Octyl acetate, 3-Octanone, 2-Hexen-1-OL, DL-Borneol, Piperitenone Oxide, alpha-Terpineol, 2-Hexenal, beta-Terpineol, Myrtenal, cis-3-Hexen-1-ol, Myrtenol, Isoamyl alcohol, 1-Hexanol, Lavandulyl acetate, Citral, Neral, Linalyl acetate, 1-Octanol, 3-Nonanol, (+ -)-Linalool, 1,8-Cineole, Citronellol, 1-Octen-3-OL, Nonanol, Geranyl acetate, Neryl acetate, 1-Decanol, 4-Terpineol and Geraniol. Based on prior in vivo validation in cancer and DIC models, Linalool, Geraniol and Citronellol were further selected for Docking. Among these, Citronellol emerged as a promising compound that can be used in combination with Dexa without compromising anti-cancer efficacy of Dox and Cardioprotective action of Dexa. TNFA, MMP2, PTGS2, JUN and HMOX1 identified as common targets between cancer and DIC with alone phytochemicals of M. arvensis. However, the key shared targets identified in both cancer and DIC alongwith phytochemicals and Dexa included TNFA, ACE, SIRT1, CDK2, and AKR1B1.

Conclusion: Phytochemicals derived from Mentha arvensis demonstrate potential as dual-action agents capable of mitigating doxorubicininduced cardiotoxicity while preserving anticancer activity. However, when used alone, these compounds exhibited only moderate therapeutic potential. Combinatorial strategies involving Dexa may enhance cardioprotective efficacy while reducing associated limitations, possibly through modulation of ferroptosis-related pathways. Nevertheless, rigorous experimental validation remains essential. Future studies should employ well-established in vivo oncogenic cardiotoxicity models incorporating Dox, Dexa, and phytochemicals concurrently to elucidate shared molecular targets and confirm therapeutic efficacy against both cancer and DIC.