Table 3:
Summary of complementary and alternative therapies evaluated for melanoma skin cancer with most available evidence.
| Agent | Mechanism of action | Effect in vitro / animal models | Effect in human participants | Potential for harm/toxicity | Level of evidence* |
|---|---|---|---|---|---|
| Botanical agents | |||||
| Tea tree oil (Melaleuca alternifolia) | • Activates caspase-dependant apoptosis | In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Slippery elm (Ulmus rubra) | • Oligonucleosomal fragmentation • Activates caspase-3 signaling pathway • Decreases expression of Bcl-2 gene and Bcl-XL gene • Increases expression of Bax gene • Propapototic effect |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Chapparel (Larrea tridentata) | • Molecular pathway not described • Tumor growth inhibition |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Alpinia galanga | • Inhibits MAPK signaling pathway • Inhibits p44/42 signaling pathway • Inhibits NF-κB signaling pathway • Antiproliferative and cytotoxic effects |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Flower buds of Lawsonia inermis (Henna) | • Inhibits TYR, TRP-1 and TRP-2 and mRNA expression • Antimelanogenesis effect |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Young green barley (Hordeum vulgare L.) | • Molecular pathway not described • Inhibits activity in melanoma cells |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| The desert plant Anastatica hierochuntica | • Inhibits phosphorylation of ERK1/2 • mRNA expression of tyrosinase and TRP-1 and −2 is contradictory • Inhibits melanogenesis |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Homeopathic mother tincture (Phytolacca decandra) | • Generates oxidative damage • Down-regulates of Akt and Bcl-2 gene • Up-regulates of Bax gene, p53, and caspase 3 signaling pathway • Antiproliferative and proapoptotic effects |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Gurmar or woody climber tree (Gymnema sylvestre) | • Causes DNA fragmentation • Increases level of mRNA expression of apoptotic signal related genes |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Hibiscus rosa-sinensis flower extract | • Induces caspases cleavages, Bcl-2 family proteins regulation, and Fas/FasL activation • Antiproliferative effects and induces autophagy |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Lingzhi (Ganoderma lucidum) | • Inhibits release of IL-8, IL-6, MMP-2, and MMP-9 • Decreases viability of melanoma cells |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Yellow jessamine (Gelsemium sempervirens) | • Down-regulates cyclin-D1, PCNA, survivin, and STAT-3 • Up-regulates of p53 and caspase-3 signaling pathway • Proapoptotic effect |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Solanum nigrum | • Decreases MMP-9, Akt activity and PKCα, Ras, and NF-κB protein expressions • Cytostatic and cytotoxic effect against human and mouse melanoma cells |
In Vitro / Mice | No | • Not reliable studies that evaluate its safety. | 5 |
| Hedyotis diffusa | • Activates caspase-3, caspase-8, and caspase-9 • Antiproliferative effect |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Panax ginseng | • Increases the production of TNF-alpha, NO and IL-6. • Regulates the C-jun N-terminal kinase phosphorylation, and p38. • Activates Akt, MAPKs, and NF-κB • Induces cell death in vitro • Reduces melanoma cell viability |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Phytochemicals | |||||
| Capsaicin | • Depletion of substance P • Inhibits PI3K, Akt, mTOR and NF-κB • Antiangioneogenisis, and proapototic effects |
In vitro | No | • Topical: Application site burning, erythema, pain, pruritus, edema, blister, scar. | 5 |
| Genistein | • Inhibits Akt, MAPK, P38 and JNK signaling pathway • Anti-angionegenisis, antiproliferative and proapototic effects |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Indole-3-carbinol | • Inhibits Akt and MITF with antiproliferative and propapoptotic effects | In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Proanthocyanidins | • Inhibits NF-κB and ERK1/2 with antiproliferative effect | In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Resveratrol | • Increases Connexin 43 gap junction communications • Decreases expression of cyclin B, cyclin D, CDK-2 and CDK-4 • Decreases expression FLIP gene, Bcl-2, and survivin • Inhibits ERK1/2 • Increases tumor suppressor protein 53 and matrix protein TSP1 • Antiproliferative effects |
In vitro | No | • May increase concentrations of pimozide (by CYP3A4 inhibition) | 5 |
| Apigenin | • ncreases ROS • Activates caspase-3 signaling pathway • Decreases phosphorylation of ERK1/2 proteins, Akt and mTOR • Antiproliferative and proapoptotic effects |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Quercetin | • Up-regulates CDK inhibitors p27(KIP1) and p21(CIP1) • Antioxidant, cell cycle arrest and proapoptotic activity |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Silymarin and silybin | • Decreases phosphorylation of ERK1/2 and RSK2, • Decreases activation of NF-κB, AP-1, and STAT3 • Increases casein kinase 1α and glycogen synthase kinase-3β • Decreases nuclear β-catenin • Inhibits of MMP-2 and MMP-9 • Antiproliferative, cell cycle arrest and proapoptotic effect |
In vitro | No | • Milk thistle (contains silymarin) may lower blood sugar levels in people with type 2 diabetes | 5 |
| Epigallocatechin-3-gallate | • Inhibits cell growth, EMT and invasion • Inhibits NF-κB signaling pathway • Decreases IL-1β secretion. inhibited iNOS, COX-2, MMPs, IL-6, IL-8, IL-12 and TNFα • Down-regulates the inflammasome • Decreases NLRP1 • Reduces caspase-1 activation Induces cell cycle arrest and apoptosis |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Chrysin | • Stimulates IL-2, IL-10 expression in mice melanoma cells | In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Paradise tree extract | • Apoptosis in melanoma cells from the A375 and G361 cell lines in-vitro | In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Berberine | • Increases melanoma cell levels of ROS and produces AMPK activation • Downregulation of ERK and p38 MAPK • Reduction in COX-2, PGE2 and PGE2 receptors |
In vitro / Mice | No | • Golden seal (contains berberine): potentially hinder glucose control in people with type 2 diabetes taking metformin (reduces 25% level) • May be safe taken alone, but there are not reliable studies that evaluate its safety. |
5 |
| Pancratistatin | • Targets mitochondrial vulverabilities • Apoptosis in melanoma cells (A375) • In combination with tamoxifen is more effective than either agent standalone (in-vitro) |
In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Curcumin | • Anti-inflammatory and anti-oxidative pathways which allow it to selectively target melanoma cells. • Up-regulates of miRNA, p53, p21(Cip1), p27(Kip1) and checkpoint kinase 2 • Down-regulates of anti-apoptotic Bcl-2, PCNA, iNOS, DNA-PKcs expression, PRL-3, anti-apoptotic Mcl-1 protein • Activates caspase-3, caspase 8, MST1 gene • Inhibits of NF-κB, PDE 1 to 5 • Inhibits phosphorylation of STAT1 and STAT3, MMP-2, mTOR activity • Increases levels of IFN-γ secretion and production of granzyme b or IFN-γ. • Reduces level of IL-12. • Akt phosphorylation has shown contradictory results. Induces MPTP opening • Multiple antioxidative, antiproliferative, proapoptotic effects on melanoma cells in vitro and murine models. • Poor bioavailability when tested in-vivo mouse models. |
In vitro / Mice | No | • Safely when taken orally but lacks bioavailability. | 5 |
| Curcuminoids | |||||
| EF24 | • Inhibits the NF-κB | In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| DM-1 | • Modulates iNOS and COX-2 gene expression | In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| D6 | • Induces overexpression of HSP and induces melanoma cells apoptosis | In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| Herbal formulas | |||||
| “Black salve” | • Induces caspase signaling pathway and oxidative stress. | In vitro | Case reports: escharotic effect. | • When added in escharotic agents: subclinical extension of tumor • Scarring and tissue damage, which could lead to disfiguring. • In melanoma has been associated with ulcer, local recurrence, and metastatic disease |
5 |
| Cannabinoids | |||||
| CB1 | • Tumor-promoting signal in human cutaneous melanoma | In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| CB1 and CB2 | • Alters Akt protein and pRb phosphorylation decreasing angiogenesis, proliferation, and metastasis of melanoma | In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| PEA | • PEA in combination with URB597 (inhibitor of fatty acid amide hydrolase) decreases melanoma progression associated with increased PEA levels | In vitro | No | • Not reliable studies that evaluate its safety. | 5 |
| THC | • Inhibits tumor growth of transplanted melanoma, inhibiting tumor growth in mice | In vitro | No | • Cannabis: risk of motor vehicle crashes, lower birth weight when consumed on pregnancy, orthostatic hypotension, severe mental illnesses (in predisposed). | 5 |
| Vitamin C | |||||
| Vitamin C | • Decreases the phosphorylated form of BRAF gene (dose dependent) • Increases the phosphorylation of ERK • Increased the phosphorylated form of AKT which mediates cell survival and growth. |
In vitro | No | • Oral: hyperoxaluria (with large doses), hemolysis (in patients with glucose-6-phosphate dehydrogenase deficiency). | 5 |
*
Level of evidence based on www.ebmconsult.com/articles/levels-of-evidence-and-recommendations