Harnessing the anticancer potential of Piper nigrum: a synergistic approach to chemotherapy enhancement and reduced side effects

Abstract

Cancer therapy continues to face critical challenges, including drug resistance, recurrence, and severe side effects, which often compromise patient outcomes and quality of life. Exploring novel, cost-effective approaches, this review highlights the potential of Piper nigrum (black pepper) extract (PNE) as a complementary anticancer agent. Piper nigrum, a widely available spice with a rich history in traditional medicine, contains bioactive compounds such as piperine, which have demonstrated significant anticancer activities including cell cycle arrest, apoptosis induction, and inhibition of tumor growth and metastasis. The review evaluates the recent findings from in vitro, in vivo, and clinical studies, emphasizing PNE's capacity to enhance the efficacy of conventional chemotherapeutic agents while mitigating their side effects. Key mechanisms underlying these effects include oxidative stress modulation, suppression of pro-metastatic factors, and synergistic interactions with established drugs like doxorubicin and paclitaxel. These interactions suggest that PNE could play a pivotal role in overcoming chemoresistance and improving therapeutic outcomes. Furthermore, this review highlights the potential benefits of PNE in resource-limited settings, where the cost of cancer treatments often restricts access. However, challenges such as compositional variability, limited bioavailability, and the need for standardization and clinical validation need to be addressed to advance the integration of PNE into basic oncology. By providing a comprehensive analysis of the anticancer mechanisms of PNE and its potential as a cost-effective adjuvant therapy, this review provides new insight into the exploitation of Piper nigrum to improve cancer treatment efficacy while reducing side effects. Future research directions are discussed to address current limitations and facilitate clinical translation.

Keywords: Piper nigrum; Anticancer; Apoptosis; Black pepper; Chemotherapy; Synergistic therapy.

Fig. 1

Mechanism of PNE in inducing cell cycle arrest and reducing tumor growth. PNE inhibit cancer cell proliferation by inducing cell cycle arrest at critical phases (e.g., G₀/G₁), reducing cell division, and downregulating growth-promoting signaling pathways. These extracts regulate key proteins, including NF-κB, cyclin B1, cyclin D1, survivin, and FoxM1, leading to decreased cancer cell division, reduced signaling for proliferation, and suppression of tumor progression. FoxM1: Forkhead Box M1; NF-κB: Nuclear Factor Kappa-light-chain-enhancer of activated B cells

Fig. 2

Apoptosis molecular mechanisms of Piper nigrum extract (PNE). PNE administration leads to decreased tumor size and growth, primarily through the induction of oxidative stress via increased ROS levels, resulting in mitochondrial dysfunction and CytC release. This process activates caspases and p53, promoting apoptosis. PNE also causes cell cycle arrest by reducing the expression of cyclins and CDK2. Additionally, PNE modulates inflammatory responses by lowering IL-4, IL-6, and IFN-γ levels, contributing to its anticancer effects. CDK2: Cyclin-dependent kinase 2, a cell cycle regulatory protein; CytC: Cytochrome c, released from mitochondria during apoptosis; IFN-γ: Interferon-gamma, a cytokine involved in immune regulation; IL-4: Interleukin-4, an anti-inflammatory cytokine; IL-6: Interleukin-6, a pro-inflammatory cytokine; p53: A tumor suppressor protein involved in apoptosis regulation; PNE: Piper nigrum extract; ROS: Reactive oxygen species, molecules causing oxidative stress; ↓decrease, ↑increase