Piperine and its nanoformulations: A mechanistic review of their anti-cancer activities
Mahsa Ghasemi, M. Hossein Nowroozzadeh, Fereshteh Ghorat, Aida Iraji, Mohammad Hashem Hashempur
Abstract
Piperine, an active compound found in black pepper, exhibits promising anti-cancer properties by targeting critical signaling pathways involved in cancer cell proliferation, migration, and invasion. This review explores the diverse mechanisms through which piperine exerts its effects, including inhibition of the PI3K/Akt/mTOR and ERK1/2 pathways, activation of p38 and JNK pathways, and suppression of NF-kB/AP-1 signaling. Piperine disrupts Wnt/β-catenin signaling by inhibiting β-catenin nuclear translocation and TCF binding, thereby impairing cancer cell growth and metastasis. Additionally, piperine demonstrates anti-inflammatory actions by reducing CXCL8 expression and modulating the p38 MAPK and JNK pathways. To overcome the issues of low solubility and bioavailability, several nanoformulations of piperine were developed, such as polymer nanoparticles, nanoemulsion, liposomes, micelles, metal-organic frameworks and inorganic carriers, establishing promising cytotoxicity, prolonged-release, enhanced cellular influx, and directed drug delivery. The mechanisms involve G₀ and G₂/M arrest of the cell cycle, mitochondria-mediated apoptosis (involving Bax/Bcl-2 modulation and caspase activation), and cancer cell death. In vivo studies underscore the efficacy of piperine, while synergistic effects with other natural products and chemotherapy highlight its potential as a versatile therapeutic agent as an anticancer agent. These findings underscore piperine's potential as a multifaceted therapeutic agent for cancer treatment, emphasizing its diverse mechanisms of action and promising role in oncology. • Piperine induces cell cycle arrest and apoptosis by regulating cyclins, CDKs, and Bax/Bcl2. • Piperine inhibits angiogenesis and metastasis by downregulating VEGF, MMPs, and Akt/mTOR signaling. • Piperine enhances drug bioavailability by inhibiting P-glycoprotein and improving absorption. • Piperine nanoformulations improve bioavailability, targeted delivery, and anticancer efficacy. • Synergistic piperine combinations with chemotherapy drugs enhance cancer treatment outcomes.