Autophagy as a targeted therapeutic approach for skin cancer: Evaluating natural and synthetic molecular interventions

Abstract

Skin cancer, a prevalent malignancy worldwide, poses significant health concerns owing to its increasing incidence. Autophagy, a natural cellular process, is a pivotal event in skin cancer and has advantageous and detrimental effects. This duality has prompted extensive investigations into medical interventions targeting autophagy modulation for their substantial therapeutic potential. This systematic review aimed to investigate the relationship between skin cancer and autophagy and the contribution and mechanism of autophagy modulators in skin cancer. We outlined the effectiveness and safety of targeting autophagy as a promising therapeutic strategy for the treatment of skin cancer. This comprehensive review identified a diverse array of autophagy modulators with promising potential for the treatment of skin cancer. Each of these compounds demonstrates efficacy through distinct physiological mechanisms that have been elucidated in detail. Interestingly, findings from a literature search indicated that none of the natural, synthetic, or semisynthetic compounds exhibited notable adverse effects in either human or animal models. Consequently, this review offers novel mechanistic and therapeutic perspectives on the targeted modulation of autophagy in skin cancer.

Keywords: Autophagy; Autophagy inducers; Autophagy inhibitors; Nature-derived compounds; Skin cancer; Synthetic compounds.

Graphical abstract

Figure 1

The five stages of autophagy are initiation, elongation and autophagosome formation, fusion, and autolysosome formation. Targeting macromolecules to double-membrane vesicles known as autophagosomes leads to autolysosome formation by lysosome fusion. The Unc-51-like autophagy-activating kinases 1 (ULK1) complex, which includes ULK, autophagy-related gene (ATG) protein 13, FIP200, and ATG101, triggers autophagy. Two ubiquitin-like conjugation systems, such as the ATG12 and microtubule-associated protein 1A/1B-light chain 3 (LC3) systems, are involved in the elongation and maturation of autophagosomes. An autolysosome is formed by the fusion of the autophagosome with the lysosome. This autolysosome breaks down macromolecules into amino acids, fatty acids, and nucleotides. ATG: Autophagy-related gene; FIP200: FAK family-interacting protein of 200 kDa; LC3: Light chain 3; PE: Phosphatidylethanolamine; ULK: Unc-51-like autophagy-activating kinase; ULK1: Unc-51-like autophagy-activating kinase 1.

Figure 2

Multifaceted role of autophagy in cancer progression. (A) Autophagy conducts homeostatic functions in normal tissue, such as monitoring the functionality of organelles and proteins. (B) When autophagy is inhibited in tissues, normal homeostasis is disrupted, which increases inflammation, reactive oxygen species (ROS) levels, and DNA damage (genomic instability and aneuploidy). Taken together, these modifications may encourage the development of tumors and trigger early tumorigenesis. (C) Autophagy accelerates oncogene-induced senescence, which inhibits malignant transformation. (D) After several stimuli, such as chemotherapy, metabolic stress, and anoikis, autophagy induction increases tumor cell survival, which may encourage drug resistance and metastasis. ROS: reactive oxygen species.

Figure 3

Chemical structures of compounds (1–18) that show efficacy against skin cancer by influencing autophagy.

Figure 4

Chemical structures of compounds (19–32) that show efficacy against skin cancer by influencing autophagy.

Figure 5

Chemical structures of compounds (33–51) that show efficacy against skin cancer by influencing autophagy.

Figure 6

Chemical structures of compounds (53–67) that show efficacy against skin cancer by influencing autophagy.