Potential of capsaicin as a combinatorial agent to overcome chemoresistance and to improve outcomes of cancer therapy

Capsaicin (CAPS), a bioactive alkaloid derived from chili peppers, has garnered significant interest for its potential role as a combinatorial and chemosensitizing agent in cancer therapy. Numerous preclinical studies have demonstrated that CAPS enhanced the efficacy of various anticancer agents by promoting apoptosis, modulating autophagy and inhibiting angiogenesis, tumor growth, and metastasis. Additionally, CAPS modulated critical regulators of chemoresistance, such as P-glycoprotein (P-gp), extracellular signal-regulated kinase (ERK), nuclear factor-kappa B (NF-κB) pathway, and signal transducer and activator of transcription 3 (STAT3) pathway, thereby contributing to the reversal of multidrug resistance (MDR). Moreover, when administered in combination with chemotherapeutic agents, CAPS has been shown to improve treatment efficacy at lower drug concentrations. Given its multitargeted mechanism of action, CAPS represents a promising adjunct to conventional cancer therapies. However, due to its lipophilic nature, the development of optimized formulation strategies is essential to enhance its bioavailability and ensure consistent therapeutic outcomes. In conclusion, CAPS holds significant potential as a combinatorial and chemosensitizing agent, helping to overcome chemoresistance and enhance treatment outcomes across various malignancies. These promising findings warrant further preclinical and clinical investigations.