Skin cancer is a major malignancy in the U.S, and its incidence is expected to go up substantially because of increased recreational exposure to sunlight and depletion of the ozone layer. Question: Is caffeine harmful or helpful in preventing skin cancer?

Two papers in the current Proceedings of the National Academy of Sciences (PNAS), released online Aug. 27, 2002, offer a choice of two contradictory findings. One report finds caffeine deleterious, the other beneficial.

On the good-news side is a report titled: "Topical applications of caffeine or epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UV induced skin tumors in mice." Its senior author is Allen Conney at Rutgers University in Piscataway, N.J.

Biochemist/oncologist Conney is director of the Laboratory for Cancer Research in the School of Pharmacy at Rutgers. "The main finding of our PNAS paper," he told BioWorld Today, "is that topical applications of either caffeine or EGCG - when given to tumor-free mice at high risk of developing skin cancer because they'd previously been treated with ultraviolet [UV] light - inhibited the formation of squamous cell carcinomas as well as keratoacanthomas.

"Mechanistically," he continued, "we also found that apoptosis was increased in the animals treated with caffeine or EGCG in their tumors but not in the normal skin surrounding those cancers. The novel aspect," Conney added, "was that selectivity of caffeine and EGCG [constituents of green and black tea] in enhancing apoptosis in tumors. We had shown previously that oral administration of caffeine or green tea inhibits skin carcinogenesis in high-risk mice. But high dose levels were required so we decided to switch from oral to topical applications, which have the potential of less side effects.

"In our in vivo experiments," Conney recounted, "we treated mice with ultraviolet light - which is present in sunlight - for 20 weeks, then stopped the UV. The pretreatment was a rather low dose of UV that didn't even cause sunburn on these hairless mice. But it did put them at high risk of developing skin cancer. It was a 30-millijoule-per-square-centimeter exposure twice a week for 20 weeks. That dosage is within the doses that people who have outdoor occupations are exposed to. It's a model of human skin cancer caused by sunlight. After stopping the UV light treatment, we started dabbing caffeine or EGCG on their skin once a day, five days a week, for 18 weeks, while monitoring the formation of skin tumors. That topical caffeine is not a sunscreen, but rather a post-sun preventive agent. At the end of the experiment, we did the histology to identify what the tumors were, and looked also for apoptosis."

Experiments Show Caffeine Curbs Skin Cancer

"Overall results of the experiments showed that treatment of the skin of these UV light pre-treated animals inhibited the formation of the skin cancers. Caffeine reduced the number of nonmalignant and malignant tumors in the mice by 44 percent and 72 percent, respectively, whereas EGCG scored 55 percent and 66 percent. Both substances appeared to act by increasing the rate of programmed cell death in tumor regions. We worked with pure chemical caffeine, which is in tea and coffee and soda pop and chocolate.

"The next step, I think," Conney went on, "points to conducting a controlled clinical trial in human patients to see whether or not individuals who have a high risk of developing skin cancers are protected by topical applications of caffeine or EGCG. Such people might be individuals who had a skin cancer removed, and would then immediately become high-risk subjects for additional skin cancers. Or people who have a lot of keratoses - premalignant lesions - on the skin.

"We're right now discussing the possibility of doing such a clinical trial in patients at high risk of developing skin cancer," Conney allowed. "We would dab on their skin some kind of lotion or cream containing pure caffeine. The putative plan for a human trial is to verify the extrapolation from mice to people. We'd also look for safety considerations, because we don't know what kind of toxicity to expect in human studies. We didn't see any in the animal studies."

In Vitro Hamster Tests Blacken Caffeine's Eye

In the bad-news corner of the same PNAS issue is the negative article titled: "Mutagenesis and repair by low doses of a radiation in mammalian cells." Its first author is molecular geneticist Theodore Puck at the Eleanor Roosevelt Institute for Cancer Research in Denver.

Puck noted, "Low doses of alpha radiation [radon] in basements and uranium mines have been causally implicated in lung cancer." He pointed out that genetic mutations caused by such low-dose radiation can be repaired during cellular division, but that caffeine inhibits this repair. The co-authors measured DNA damage and repair in hamster cells that had been exposed to low doses of either alpha or gamma (high-energy) radiation. They examined the cells during the G2 stage of the cell cycle when mitotic chromosomes shrink 20,000-fold. That permits the discerning of the presence of genetic damage in the form of DNA "breaks and gaps."

When caffeine was applied to the cells after alpha and gamma irradiation, similar levels of mutation ensued. In the absence of caffeine, however, mutations caused by alpha irradiation decreased sharply. These results show that "caffeine prevents repair of alpha-ray-induced mutations in a fashion generally similar to that previously described with gamma [high-energy] rays." The paper concluded: "Low-dose alpha radiation originating from radon in basements of human dwellings has been implicated in a significant percentage of human lung cancer, and alpha radiation originating from uranium has been associated with very high incidence of lung cancer in miners, particularly those who smoke cigarettes."

Commenting on the bad-news companion PNAS paper, Conney observed, "Puck is getting an effect to inhibit DNA repair from alpha radiation, and these are in cultured hamster cells, which is interesting. In vitro cell cultures are somewhat distant from in vivo animal studies. What one sees in cell culture doesn't always occur in animals, just as what occurs in animals," he concluded, "doesn't always occur in people."