Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines—which represent much of the tissue-type and genetic diversity of human cancers—with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing’s sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

Background: Excessive human exposure to solar ultraviolet radiation (UVR) continues to be a major public health concern, with skin cancer rates increasing year on year. The major protective measure is the use of synthetic UVR filters formulated into sunscreens, but there is a growing concern that some of these chemicals cause damage to delicate marine ecosystems. One alternative is the use of biocompatible mycosporine-like amino acids (MAA), which occur naturally in a wide range of marine species. Their role within nature is mainly thought to be photoprotective. However, their potential for human photoprotection is largely understudied. Objective: To review the role of MAA in nature and assess their potential as natural sunscreens for human skin photoprotection. Method: A literature review of all relevant papers was conducted. Conclusion: MAA are natural photostable compounds that are thought to offer photoprotection to marine species. Initially thought of as protective based on their absorption properties in the solar UVR spectrum, it is clear that MAA are multifunctional photoprotective compounds acting as chemical and biological anti-oxidants. This suggests that MAA may offer a novel eco-friendly approach to human skin photoprotection. Most studies have been carried out in vitro and current data strongly suggest that MAA have potential for development as natural biocompatible sunscreens that protect against a diverse range of solar UVR induced adverse effects on human health.

The adverse effects of terrestrial solar ultraviolet radiation (UVR) (~295–400 nm) on the skin are well documented, especially in the UVB region (~295–320 nm). The effects of very long-wave UVA (>380 nm) and visible radiation (≥400 nm) are much less known. Sunscreens have been beneficial in inhibiting a wide range of photodamage, however most formulations provide very little protection in the long wave UVA region (380–400 nm) and almost none from shortwave visible wavelengths (400–420 nm). We demonstrate photodamage in this region for a number of different endpoints including cell viability, DNA damage (delayed cyclobutane pyrimidine dimers), differential gene expression (for genes associated with inflammation, oxidative stress and photoageing) and induction of oxidizing species in vitro in HaCaT keratinocytes and in vivo in human volunteers. This work has implications for phototherapy and photoprotection.

Background Sunlight contains UVA and UVB radiation. The latter is essential for vitamin D synthesis but is the main cause of sunburn and skin cancer. Sunscreen use is advocated to reduce the sun's adverse effects but may compromise vitamin D status. Methods The impact of sunscreens on vitamin D status was studied during a one‐week sun‐holiday in Tenerife (28°N). Comparisons were made between two formulations, each with a sun protection factor of 15. The UVA protection factor (UVA‐PF) was low in one case and high in the other. Healthy Polish volunteers (n=20 per group) were given the sunscreens and advised on correct application. Comparisons were also made with discretionary sunscreen use (n=22) and non‐holiday groups (51^o5N, n=17). Sunscreen use in the intervention groups was measured. Behaviour, UVR exposure, clothing cover and sunburn were monitored. Serum 25(OH)D, was assessed by HPLC MS/MS. Results Use of intervention sunscreens was the same (p=0.599) and both equally inhibited sunburn, that was present in the discretionary use group. There was an increase (p=9x10^‐8) of 28.0±16.5(SD) nmol/L 25(OH)D₃ in the discretionary use group. The high and low UVA‐PF sunscreen groups showed statistically significant increases (p≤6.7x10^‐5) of 19.0±14.2 and 13.0±11.4 nmol/L 25(OH)D₃ respectively. The non‐holiday group showed a fall (p=0.08) of 2.5±5.6 nmol/L 25(OH)D₃. Conclusions Sunscreens may be used to prevent sunburn yet allow vitamin D synthesis. A high UVA‐PF sunscreen enables significantly higher vitamin D synthesis than a low UVA‐PF sunscreen because the former, by default, transmits more UVB than the latter.

Mycosporine-like amino acids (MAAs) are UVR-absorbing metabolites typically produced by cyanobacteria and marine algae, but their properties are not limited to direct sun screening protection. Herein, we examine the antioxidant activities of porphyra-334 and shinorine and demonstrate that these MAAs are prospective activators of the cytoprotective Keap1-Nrf2 pathway. The ability of porphyra-334 and shinorine to bind with Keap1 was determined using fluorescence polarization (FP) and thermal shift assays to detect Keap1 receptor antagonism. Concomitantly, the ability of porphyra-334 and shinorine to dissociate Nrf2 from Keap1 was confirmed also by measurement of increased mRNA expression of Nrf2 targeted genes encoding oxidative stress defense proteins in primary skin fibroblasts prior and post UVR exposure. Surprisingly, enhanced transcriptional regulation was only promoted by MAAs in cells after exposure to UVR-induced oxidative stress. Furthermore, the in-vitro antioxidant activities of porphyra-334 and shinorine determined by the DPPH free-radical quenching assay were low in comparison to ascorbic acid. However, their antioxidant capacity determined by the ORAC assay to quench free radicals via hydrogen atom transfer is substantial. Hence, the dual nature of MAAs to provide antioxidant protection may offer a prospective chemotherapeutic strategy to prevent or retard the progression of multiple degenerative disorders of ageing.

Background Solar ultraviolet radiation (UVR) induces molecular and genetic changes in the skin, which result in skin cancer, photoageing and photosensitivity disorders. The use of sunscreens is advocated to prevent such photodamage; however, most formulations contain organic and inorganic UVR filters that are nonbiodegradable and can damage fragile marine ecosystems. Mycosporine-like amino acids (MAAs) are natural UVR-absorbing compounds that have evolved in marine species for protection against chronic UVR exposure in shallow-water habitats. Objectives To determine if palythine, a photostable model MAA, could offer protection against a range of UVR-induced damage biomarkers that are important in skin cancer and photoageing. Methods HaCaT human keratinocytes were used to assess the photoprotective potential of palythine using a number of end points including cell viability, DNA damage (nonspecific, cyclobutane pyrimidine dimers and oxidatively generated damage), gene expression changes (linked to inflammation, photoageing and oxidative stress) and oxidative stress. The antioxidant mechanism was investigated using chemical quenching and Nrf2 pathway activation assays. Results Palythine offered statistically significant protection (P < 0·005) against all end points tested even at extremely low concentrations (0·3% w/v). Additionally, palythine was found to be a potent antioxidant, reducing oxidatively generated stress, even when added after exposure. Conclusions Palythine is an extremely effective multifunctional photoprotective molecule in vitro that has potential to be developed as a natural and biocompatible alternative to currently approved UVR filters.