42 SUN CARE
interacts with MC1R receptors on melanocytes to increase the activity of tyrosinase, the rate- limiting enzyme in melanin synthesis. The newly synthesized melanin is packaged in intracellular vesicles called melanosomes, which are transported from the melanocytes via their dendrites to keratinocytes, manifest as tanning (adaptive hyperpigmentation). As skin cancer is far less common in races with dark skin than in those with fair skin, synthetic agonists that bind to the MC1R receptors to mimic the effect of α-MSH might be expected to prevent skin cancer by boosting the skin’s natural defences. However, to date no such molecule has been successfully developed. Although polypeptide analogues of
α-MSH have been synthesized, one of which is approved by the FDA for reducing cutaneous photosensitivity in an hereditary form of porphyria when given by subcutaneous injection, none is considered to be safe for unregulated use as a photo-protective in the general population, owing to concerns about off-target effects and the possibility of melanoma induction.54
An ideal sunscreen? Are there ways in which currently available molecules could be improved? Dahabra et al have discussed how cyclodextrins might be used to increase the stability and bioavailability of UV screens and anti-oxidants.55
The
molecules of these cyclic oligosaccharides are like hollow truncated cones of different sizes, according to whether they are composed of 6, 7, or 8 glucopyranose units. Having a hydrophilic exterior and
hydrophobic interior, they are able to accommodate lipophilic UV filters and anti-oxidants (e.g., flavonoids, polyphenols, and carotenoids) of different molecular sizes. Although this might well improve the performance of some actives, increases in SPF number are unlikely to confer significant improvement in UVB filtration, given that SPF50 already blocks 98%. Furthermore, the problems of non-biodegradability and harmful effects on the environment would remain. Theoretically, the ideal sunscreen would
attenuate wavelengths extending from UVB to the infrared/visible border and be photo-stable, non-allergenic, non-absorbable into the blood, biodegradable, and environmentally friendly. No molecule satisfying all these criteria has
yet been created by chemists or discovered. Obvious places to look in nature are species inhabiting environments where there is strong sunlight, where molecules conferring protection against solar radiation would presumably have provided evolutionary advantage. The first natural chemical to be used as a
UV screen was the cinchona alkaloid quinine. However, most molecules with UV absorption properties in higher plants are flavonoids or cinnamates, some of which are already used in consumer products.56
Yet it is in aquatic plants
that the most promising natural UV screens have been found. Mycosporine-like amino acids are produced by certain seaweeds, micro-algae, corals, and
PERSONAL CARE April 2024
Figure 2: Four marine species of interest in relation to skin cancer prevention. A: The red alga Gelidium synthesizes a mycosporine-like amino acid with UV-filtering activities. B: The microalga Chlamydomonas synthesizes the enzyme photolyase, which repairs DNA damaged by UVB radiation. C: Corals, which are critically important for the viability of seagrass meadows, are bleaching in many parts of the world. Several UV screens have been shown to induce DNA mutations and activate latent virus infections in corals, leading to expulsion of the symbiotic zooxanthellae. D: Seagrass, which captures carbon many times faster than tropical rainforests, and whose global biomass is declining, are accumulating UV screens, reducing chlorophyll synthesis and nitrogen fixation
cyanobacteria, especially during exposure to strong sunlight.57
Their absorption spectra
cover much of the UVA and UVB wavelengths, typically peaking at 270 and 365 nm. Unlike cinnamates, flavonoids, and synthetic UV screens, mycosporine-like amino acids are also photo-stable.
Dissipating the absorbed energy as
heat, they do not undergo isomerization, dimerization, interactions with each other, or photo-decomposition in the manner of some other UV screens.58
They also have some
antioxidant activity. However, as they are very water soluble,
they are likely to be rapidly lost during sweating, bathing, and swimming. Furthermore, as both their extraction from the only abundant natural sources, seaweeds and micro-algae, and their industrial synthesis are challenging, their commercial viability is uncertain.
Photolyases Another class of natural molecules of interest is a category of enzymes known as photolyases.59 Like mycosporine-like amino acids, they are found in species regularly exposed to strong sunlight, including some algae, fish, amphibians, reptiles, and bacteria. Yet they are not produced in humans, other mammals, or higher plants. They have the specific function of repairing
the two types of DNA lesion that are most commonly produced by the direct action of UVB: cyclobutane pyrimidine dimers and pyrimidine-pyrimidone (6–4) photoproducts.
In humans, most such lesions are repaired by nucleotide excision repair, a less efficient process. Counter-intuitively, photolyases require
blue light to catalyse a process called photo- reactivation, which has been shown in cultured keratinocytes to reverse DNA lesions produced by UVB irradiation.60
Although their potential
utility in skin cancer prevention is limited by their molecular size of 450-550 amino acids, this hurdle might be surmountable by incorporation into liposomes or other types of nanoparticle. Even if a small molecule with photolyase
activity were developed, it would only protect against UVB-induced lesions in DNA, and not those caused by ROS generated by UVA, infrared, and visible radiations.31-35
Nor would
it protect against the increasingly important additional source of ROS to which the skin exposed, namely atmospheric pollution, to which the WHO has concluded 90% of the world’s population is now exposed. Nitrogen dioxide, ozone, polycyclic aromatic
hydrocarbons, tobacco smoke, and small particles (PM10 and PM2.5) have all been shown to generate ROS and damage DNA.61, 62
The extent
to which urban and industrial pollution cause skin cancers is not known, but a contribution seems very likely given the experimental evidence that atmospheric pollutants and solar radiation are synergistic in their effects on DNA.63 Given the multiple sources of ROS to which
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