Targeting Skin Neoplasms: A Review of Berberine's Anticancer Properties

Abstract

Skin cancers are associated with a significant psychological burden across all age groups, particularly as their global incidence continues to rise. Ultraviolet (UV) radiation-primarily UVA and UVB-remains the leading etiological factor, inducing DNA mutations in key genes such as TP53 and BRAF. Among skin cancers, basal cell carcinoma (BCC) is the most prevalent and typically indolent. In contrast, squamous cell carcinoma (SCC) tends to be more invasive, while melanoma is the most aggressive and prone to metastasis. Melanoma is especially concerning due to its rapid dissemination and its occurrence not only on the skin but also in ocular, mucosal, and nail tissues. These challenges, along with rising treatment resistance and mortality, underscore the urgent need for novel anticancer agents. Berberine-a plant-derived isoquinoline alkaloid-has attracted increasing attention for its broad-spectrum anticancer potential, including against skin cancers. In this review, we summarize current evidence regarding berberine's mechanisms of action in melanoma and SCC, emphasizing both its preventive and therapeutic effects. We further explore its potential as an adjuvant agent in combination with conventional treatments, offering a promising avenue for enhancing the clinical outcomes of skin cancer therapy.

Keywords: adjuvant therapy; anticancer activity; berberine; melanoma; natural compounds; skin neoplasms; squamous cell carcinoma.

Figure 1

Classification of skin cancers with special regard to melanoma phenotypes and representatives of non-melanoma skin cancers (NMSC). Abbreviations: ALM—acral lentiginous melanoma, BCC—basal cell carcinoma, BCL—B-cell lymphoma, CTCL—cutaneous T-cell lymphoma, LM—lentigo melanoma, MCC—Merkel cell carcinoma, NM—nodular melanoma, NMSC—non-melanoma skin cancer, SCC—squamous cell carcinoma, SSM—superficial spreading melanoma.

Figure 2

Micro-structure of the skin with a special regard to the histological image of the layers of epidermis and start points of skin cancer proliferation (simplified scheme).

Figure 3

Overactivity of the Hedgehog signaling pathway associated with BCC development (simplified scheme). Abbreviations: BCC—basal cell carcinoma, GLIs—glioma-associated oncogenes, PTCH1—gene encoding the patched homolog 1 protein, SMO—Smoothened gene.

Figure 4

Molecular roles of selected tp53-mediated cellular pathways under normal conditions (simplified scheme). Abbreviations: AMPK—5′-adenosine monophosphate-activated protein kinase, Bax—apoptosis regulator BAX; Bcl-2, Bcl-w, and Bcl-xL—pro-apoptotic factors, Cdk—cyclin-dependent kinase, DRAMs—damage-regulated autophagy modulators, HIF-1α—hypoxia-inducible factor 1 α, Mcl-1—pro-apoptotic factor Mcl-1, mTOR1C—mammalian target of rapamycin 1C, NOXA—phorbol-12-myristate-13-acetate-induced protein 1, PUMA—p53 upregulated modulator of apoptosis, p21—cyclin-dependent kinase inhibitor 1, p53—tumor suppressor protein p53, SCL7A11—cystine/glutamate transporter-encoding gene, TSP1—thrombospondin 1, ULK1—serine/threonine-protein kinase ULK1.

Figure 5

The main signaling pathways affected in melanoma. Abbreviations: Akt—protein kinase B, BRAF—v-Raf murine sarcoma viral oncogene homolog B, ERK—extracellular signal-regulated kinase, GTP—guanosine triphosphate, MEK—mitogen-activated protein kinase kinase, mTOR—mammalian target of rapamycin, NF1—neurofibromin 1, NRAS—neuroblastoma RAS viral oncogene homolog, PTEN—phosphatase and tensin homolog, RAS—rat sarcoma virus kinase, RTK—receptor tyrosine kinase.

Figure 6

Molecular structure of berberine.

Figure 7

Simplified diagram of the mechanism of the anticancer activity of BBR through the inhibition of the PI3K/AKT/mTORpathway [50,53,56,57]. Abbreviations: Arrows represent activation, and bars indicate inhibition. RTK—receptor tyrosine kinase.

Figure 8

The embryonic development and differentiation of melanocytes.

Figure 9

Spectrum of the molecular effects of berberine on melanoma cells. Abbreviations: EMT—epithelial–mesenchymal transition, CisPt—cisplatin, BBR-PDT—berberine–photodynamic therapy, ROS—reactive oxygen species, ER—endoplasmic reticulum, CHOP—apoptosis-related protein, EVO—evodiamine, BBR—berberine, DOX—doxorubicin, NQO1—quinone oxidoreductase 1, DCs—dendritic cells.

Figure 10

The relation between BBR and intrinsic apoptosis.