Piperine\'s Molecular Characteristics in Inflammatory Signaling Pathways in Head and Neck Cancer

Kalius Quasi^*
*Correspondence: Kalius Quasi, Department of Health and Medical Science, Bond University, Robina, QLD 4226, Australia, Email:

Introduction

Piperine, a bioactive alkaloid found predominantly in black pepper (Piper nigrum), has garnered significant attention in recent years for its diverse pharmacological properties. Among these, its potential anti-cancer effects, particularly in Head and Neck Cancer (HNC), have been the subject of intense research. Head and neck cancers, which include malignancies of the oral cavity, pharynx, and larynx, present a significant clinical challenge due to their aggressive nature and resistance to conventional therapies. Inflammatory signaling pathways are known to play a critical role in the pathogenesis and progression of these cancers. This review aims to explore the molecular characteristics of piperine and its impact on inflammatory signaling pathways in head and neck cancer [1].

Description

Piperine is an alkaloid characterized by its pungent taste and is chemically known as 1-piperoylpiperidine. Its molecular formula is C₁₇H₁₉NO₃, and it has a molecular weight of 285.34 g/mol. The structure of piperine consists of a piperidine ring bonded to a methylenedioxyphenyl moiety via a double-bonded chain. This unique structure contributes to its bioavailability and interaction with various biological targets. Piperine is relatively hydrophobic, facilitating its passage through cellular membranes and enhancing its bioavailability. This property also allows piperine to interact with a range of intracellular proteins and signaling molecules, thereby influencing multiple cellular pathways. Chronic inflammation is a well-recognized hallmark of cancer, contributing to various stages of tumorigenesis, including initiation, promotion and progression [2].

Nuclear Factor kappa B (NF-κB) Pathway is a transcription factor that regulates the expression of genes involved in inflammation, immune response, cell proliferation, and survival. Dysregulation of NF-κB signaling is common in HNC, leading to increased production of pro-inflammatory cytokines, chemokines, and survival signals. Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) Pathway is crucial for mediating responses to cytokines and growth factors. Aberrant activation of this pathway has been linked to enhanced tumor growth, survival, and immune evasion in HNC. Cyclooxygenase-2 (COX-2) Pathway is an enzyme involved in the synthesis of prostaglandins, which are lipid compounds that mediate inflammation. Overexpression of COX-2 in HNC is associated with increased angiogenesis, tumor growth, and resistance to apoptosis. Mitogen-Activated Protein Kinase (MAPK) Pathway pathway regulates cell proliferation, differentiation, and survival. In HNC, this pathway often becomes dysregulated, leading to uncontrolled cell growth and survival [3].

Piperine has been shown to inhibit the NF-κB pathway, which plays a pivotal role in the inflammatory response and cancer progression. Piperine achieves this by preventing the phosphorylation and degradation of IκBα, an inhibitor of NF-κB. By stabilizing IκBα, piperine effectively inhibits the nuclear translocation and DNA binding activity of NF-κB. This results in decreased expression of NF-κB target genes, including those encoding pro-inflammatory cytokines (e.g., TNF-α, IL-6), chemokines (e.g., IL-8), and anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL). In head and neck cancer cells, piperine's inhibition of NF-κB signaling has been correlated with reduced cell proliferation, migration, and invasion, as well as increased apoptosis. For instance, studies have demonstrated that piperine suppresses the growth of Oral Squamous Cell Carcinoma (OSCC) cells by downregulating NF-κB activity and its downstream targets. This suggests that piperine may serve as a potential therapeutic agent for targeting NF-κB-driven inflammation in HNC [4].

The JAK/STAT pathway is another critical signaling cascade modulated by piperine. Piperine inhibits the activation of STAT3, a key transcription factor within this pathway, by preventing its phosphorylation. Activated STAT3 promotes the transcription of genes involved in cell proliferation, survival, and immune evasion. By inhibiting STAT3 phosphorylation, piperine reduces the expression of these genes, thereby impairing cancer cell growth and survival. In HNC models, piperine's inhibition of the JAK/STAT pathway has been shown to decrease tumor growth and enhance the sensitivity of cancer cells to chemotherapeutic agents. Additionally, piperine has been reported to induce apoptosis in HNC cells through downregulation of STAT3 and its target genes, such as Bcl-2 and Cyclin D1. Piperine also exerts its anti-inflammatory and anti-cancer effects through modulation of the COX-2 pathway. COX-2 overexpression is common in HNC and is associated with poor prognosis. Piperine inhibits COX-2 expression and activity, leading to reduced production of prostaglandins, which are key mediators of inflammation and tumor progression. By downregulating COX-2, piperine reduces angiogenesis, tumor growth, and metastasis in HNC. Studies have shown that piperine treatment decreases the levels of COX-2 and its product, prostaglandin E2 (PGE2), in HNC cells, resulting in impaired tumor vascularization and growth. This suggests that targeting COX-2 with piperine could be an effective strategy for managing inflammation-driven HNC. The MAPK pathway, which includes the ERK, JNK, and p38 MAPK cascades, is crucial for regulating cell proliferation, differentiation, and survival. Piperine has been shown to inhibit the MAPK pathway by targeting multiple components of this signaling cascade. In HNC, piperine inhibits the phosphorylation of ERK, JNK, and p38 MAPKs, leading to decreased cell proliferation and increased apoptosis. For example, studies have demonstrated that piperine treatment reduces the activation of ERK1/2 and p38 MAPK in OSCC cells, resulting in impaired cell growth and survival. This indicates that piperine can effectively disrupt MAPK signaling to suppress tumor progression in HNC [5].

Conclusion

The anti-inflammatory and anti-cancer properties of piperine make it a promising candidate for the treatment of head and neck cancer. Its ability to target multiple inflammatory signaling pathways suggests that piperine could be used as a multi-targeted therapeutic agent, either alone or in combination with existing treatments. Piperine exhibits potent anti-inflammatory and anti-cancer properties by targeting multiple signaling pathways involved in the pathogenesis and progression of head and neck cancer. By modulating the NF-κB, JAK/STAT, COX-2, and MAPK pathways, piperine reduces inflammation, tumor growth, and metastasis.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Abraham, Zephania Saitabau, Kisula Mchele and Aveline Aloyce Kahinga. "Awareness of head and neck cancer among patients attended at a regional referral hospital in Tanzania." BMC Public Health 23 (2023): 1544.

Google Scholar, Crossref, Indexed at

2. Naeem, Abid, Pengyi Hu, Ming Yang and Jing Zhang, et al. "Natural products as anticancer agents: Current status and future perspectives." Molecules 27 (2022): 8367.

Google Scholar, Crossref, Indexed at

3. Azam, Shofiul, Ju-Young Park, In-Su Kim and Dong-Kug Choi. "Piperine and its metabolite’s pharmacology in neurodegenerative and neurological diseases." Biomedicines 10 (2022): 154.

Google Scholar, Crossref, Indexed at

4. Jackel, Luise, Arianne Schnabel, Hagen Stellmach and Ulrike Klauß, et al. "The terminal enzymatic step in piperine biosynthesis is co‐localized with the product piperine in specialized cells of black pepper (Piper nigrum L.)." The Plant Journal 111 (2022): 731-747.

Google Scholar, Crossref, Indexed at

5. Haris, P., Varughese Mary, M. Haridas, and C. Sudarsanakumar. "Energetics, thermodynamics and molecular recognition of piperine with DNA." J Chem Inf Mod 55 (2015): 2644-2656.

Google Scholar, Crossref, Indexed at