α-Phellandrene, (1,isopropyl-2-methylcyclohexa-1,4-diene) is a naturally occurring monoterpene hydrocarbon that's used to make essential oils from plants including eucalyptus, ginger, and some citrus fruits. The structure is of the cyclic diene form, with distinct aromatic and chemical characteristics. α-Phellandrene is C10H16 in structure, and it is a clear, colorless liquid with a clean, lemony scent. It is also optically active, available in (+) and (-) enantiomers, hence the variety of industrial uses..
Fig.1 Representative plant species reported to have α-phellandrene[1].
Due to its broad biological activities and distinct molecular mechanisms, it is a molecule of interest for therapeutic applications. However, α-phellandrene also presents specific safety concerns that warrant detailed examination. This article explores α-phellandrene's mechanisms of action in inflammation and cancer, recent advances in its anticancer research, and a comprehensive safety assessment.
Anti-Inflammatory Mechanisms
α-phellandrene exerts anti-inflammatory effects by modulating multiple cellular pathways and molecular targets. Key mechanisms include:
- NF-κB Blocker: α-phellandrene blocks nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a transcription factor that induces expression of pro-inflammatory genes. Since α-phellandrene shuts down NF-κB, it lowers inflammatory mediators to lessen inflammation.
- Increased Pro-inflammatory Cytokine Activity: In vitro, α-phellandrene significantly inhibits pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), especially in LPS-stimulated macrophages. Also, α-phellandrene modulates other inflammatory mediators like leukotriene B4, interleukin-8 (IL-8), and complement component C5a, which is another anti-inflammatory activity of -phellandrene.
- Contamination of Pro-inflammatory Enzymes: Anti-inflammatory properties of α-phellandrene are also induced by inhibition of pro-inflammatory enzymes to prevent the production and excretion of inflammation-related chemicals.
- Repression of Neutrophil Infiltration and Mast Cell Degranulation: α-phellandrene inhibits neutrophil infiltration and mast cell degranulation, two process involved in the uptake of inflammatory responses.
- Controlling Leukocyte Rolling and Adhesion: By reducing leukocyte rolling and adhesion to the endothelium, α-phellandrene reduces leukocyte attraction to irritated tissue and therefore reduces the inflammatory response.
- Limitation of Oxidative Stress: α-phellandrene reduces reactive oxygen species (ROS) including nitric oxide (NO) and superoxide anions (O2-) in cells, which decreases oxidative stress that is a major source of chronic inflammation. It is a system for healing wounds and tissue.
- Positioning of Opioid Receptors: There is some evidence that α-phellandrene can activate opioid receptors, decreasing chronic pain. This pain relieving property is in turn a factor in its anti-inflammatory properties, because pain is the natural side-effect of inflammation.
Fig.2 Neurotoxicity of α-phellandrene: (A) insecticide by neurotoxicity in larvae. (B) Antibacterial action by increasing permeability of microbial cell membrane and ion leakage. (C) Anti-nociceptive effects through neurotransmitter modulation through opioid, GABA and cholinergic systems. (D) Immune enhancement through macrophage and NK cell activation, and T- and B-cell proliferation. (E) Anti-cancer action by inducing autophagy and DNA damage. (F) Anti-inflammatory effects by reducing TNF-α, IL6, and preventing mast cell degranulation. (G) Promotes wound healing by inhibiting COX II, and LOX 5, and activating fibroblast migration[1].
Advances in Anticancer Research
But now that α-phellandrene has been studied, it's been found to be an effective complement to chemotherapy against many types of cancer, including colorectal, liver, and breast cancer..
Enhancement of Chemotherapeutic Efficacy:
α-phellandrene increases the activity of chemotherapeutics including 5-fluorouracil (5-FU) on colon cancer cells (HT-29). This is accomplished by the modulation of cell cycle proteins, induction of mitochondrial apoptotic machinery (e.g., Bcl-2 family proteins, caspases), and initiating extrinsic apoptotic signalling (e.g., caspase-8 and caspase-3) that together stop cancer cells from growing.
Induction of Necrosis in Hepatocellular Carcinoma Cells:
α-phellandrene necrosises hepatocellular carcinoma cells, but changes the expression of genes that cause DNA damage, cell cycle control and apoptosis in parallel. According to this result, α-phellandrene could be used as a treatment for liver cancer.
Anticancer Action Across the Board and Immune Regulation:
Outside of individual tumors, α-phellandrene is an anticancer in lung, breast, prostate, and liver cancers. It increases immune cell proliferation (B and T cells) and boosts phagocytic activity (macrophages) and natural killer (NK) cell cytotoxicity (a component of anti-tumor immunity). -phellandrene has also been shown to inhibit leukemia cells, which is another indication that it can be an immune-suppressive anticancer.
Molecular Docking and Toxicity Studies:
Computational studies show potent and consistent interactions between α-phellandrene and molecular targets like transient receptor potential vanilloid 1 (TRPV1) and opioid receptors (μ and δ). These interactions support the hypothesis of its antitumor, analgesic, and immune-modulating activities. Additionally, α-phellandrene displays dose-dependent cytotoxicity in U87 glioblastoma cells, with an initial inhibitory concentration of 31.25 µg/mL, indicating its potential to suppress tumor growth.
Autophagy Induction:
Another key mechanism involves α-phellandrene's induction of autophagy, a cellular process essential for clearing damaged components and responding to stress. This property may enhance cell survival under stress while selectively removing cancer cells, providing a novel therapeutic angle.
Fig.2 (A) Effect of α-phellandrene combined with 5‑FU treatment on HT‑29 cell viability and apoptosis. (B) Morphological examination of HT‑29 cells. (C) Immunocytochemical staining with Annexin V (green) and PI (red)[2].
Safety Assessment
While α-phellandrene has therapeutic benefits, it is essential to evaluate its safety, particularly due to its potential toxicity and environmental hazards.
| Parameter | Safety Rating | Recommendations |
| Oral Toxicity (LD50 in rats) | Moderate (5700 mg/kg) | Use with caution in oral applications |
| Skin Irritation | Low | Minor irritation possible; recommend protective gloves |
| Eye Irritation | Low | Generally non-irritant; eye protection recommended |
| Respiratory Hazard | High | Use in well-ventilated areas with respiratory protection |
| Aquatic Toxicity (Water Hazard) | Very High | Prevent water contamination; manage spills effectively |
| Flammability | High | Keep away from heat, sparks, open flames |
References
- A Narrative Review on the Bioactivity and Health Benefits of α-Phellandrene. Scientia Pharmaceutica (2022).
- α-Phellandrene Enhances the Apoptosis of HT‑29 Cells Induced by 5-Fluorouracil by Modulating the Mitochondria-dependent Pathway. ONCOLOGY REPORTS (2024).
