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Discussion
α-Lactalbumin–oleic acid is a protein–lipid complex that induces apoptosis-like death in transformed cells in vitro. In this study, designed as a proof of principle, we investigated the effect of α-lactalbumin–oleic acid on skin papillomas. Forty patients and a total of 166 papillomas were treated according to a randomized, placebo-controlled protocol. α-Lactalbumin–oleic acid reduced the lesion volume by at least 75 percent in all 20 patients assigned to this treatment and in 96 percent of the papillomas, as compared with 15 percent of patients and 20 percent of lesions in the placebo group (P<0.001). The lesions in the placebo group responded to subsequent treatment with α-lactalbumin–oleic acid, with a median reduction in lesion volume of 82 percent. With time, all lesions resolved completely in most of the patients who received α-lactalbumin–oleic acid (29 of 35 patients [83 percent]), and these patients were still free of lesions at the two-year follow-up. These results establish that α-lactalbumin–oleic acid is active in humans.
In the past, the treatment of papillomas has had limited success. Salicylic acid has a cure rate of about 75 percent, as compared with 48 percent in placebo groups,
11 but in most studies, lesions persist despite rigorous treatment. Resistance to treatment is influenced by the HPV type and the viral load. We enrolled patients with lesions that were resistant to conventional therapies. The relatively low rate of spontaneous cure in the placebo group, compared with the rates in earlier studies, could reflect this selection factor. On the other hand, treatment with α-lactalbumin–oleic acid was effective in most patients despite the prior failure of conventional therapies. After two three-week courses of α-lactalbumin–oleic acid (one three-week course in the group that received placebo in the first phase of the study), α-lactalbumin–oleic acid appeared to be at least as effective as conventional therapies.
This exploratory study of the therapeutic potential of α-lactalbumin–oleic acid leaves a number of issues unresolved. Most important, the absorption of α-lactalbumin–oleic acid through the stratum corneum of papillomas has not been studied. Distribution experiments in intact papillomas might be conducted with the use of laser-based techniques to trace fluorescently labeled α-lactalbumin–oleic acid in intact lesions in vivo. However, α-lactalbumin–oleic acid has been shown to penetrate through tumor-biopsy specimens and to diffuse throughout entire brain hemispheres after intracerebral delivery in rats.
16 It will also be essential to use biopsy material to investigate whether α-lactalbumin–oleic acid penetrates papilloma tissue and induces apoptosis in vivo.
The effect of α-lactalbumin–oleic acid on tumor cells and transformed cell lines was discovered by chance when a lung-cancer cell line was exposed to a human milk fraction obtained by low pH treatment.
12After extensive purification, the activity was attributed to α-lactalbumin in a partially unfolded conformation stabilized by a lipid cofactor that was identified as oleic acid (C18:1Δ9).
13 By deliberate unfolding and addition of the fatty acid cofactor, our group was able to convert native α-lactalbumin to α-lactalbumin–oleic acid, and the complex was defined as a novel molecular entity, comprising these two components.
13 The results illustrate how proteins can adopt new functions by changing their conformation in response to new environments, which also supply the appropriate cofactors. The present study exemplifies the way in which such beneficial folding variants might be used to treat disease.
α-Lactalbumin–oleic acid activates several aspects of the cell-death machinery. In tumor cell lines, this complex crosses the cell membrane and moves through the cytoplasm to the nucleus, where it accumulates and disrupts the chromatin.
17 Such nuclear accumulation does not occur in healthy cells, which remain viable in the presence of α-lactalbumin–oleic acid. Tumor cells release cytochrome
c and activate caspases in response to α-lactalbumin–oleic acid,
18,19 but cell death does not appear to be regulated by the classic apoptosis pathways; α-lactalbumin–oleic acid kills tumor cells in vitro, regardless of their p53 status, and cell lines with wild-type, null, or mutant p53 genotypes do not differ in susceptibility to α-lactalbumin–oleic acid.
14 The effect of α-lactalbumin–oleic acid on HPV-infected cells was therefore not unexpected. The
E6 and
E7 genes of HPV type 16 and type 18 have been shown to immortalize infected cells by inactivating p53, but this step should not influence the response to α-lactalbumin–oleic acid.
Interestingly, α-lactalbumin–oleic acid elevates the concentration of intracellular calcium ions,
12 and calcium-ion fluxes have been shown to stimulate terminal differentiation of keratinocytes.
20 We speculate that α-lactalbumin–oleic acid may act both by inducing apoptosis-like death in rapidly proliferating cells and by turning on the differentiation program that is halted in the transformed keratinocytes in papillomas. Further experiments in keratinocytes are required to address these questions.
The effectiveness of α-lactalbumin–oleic acid in the immunosuppressed patients in our study is important, since immunosuppression is known to increase susceptibility to many viral agents, including HPV.
7–9 Most people are infected by HPV during their lifetimes and may become carriers, but immunosuppressed patients tend to have lesions that are difficult to eradicate, and their treatment is a major problem. Papillomas develop in 90 percent of renal-transplant recipients, for example, within five years after transplantation.
21 The efficacy of α-lactalbumin–oleic acid in immunosuppressed patients is consistent with the proposed mechanism of action, since the clearance of apoptotic cells is carried out by the innate defense system and does not require a specific immune response. Topical α-lactalbumin–oleic acid might thus offer a substantial improvement in treatment for immunosuppressed patients with papillomas, who currently rely on laser therapy or other invasive methods.
α-Lactalbumin–oleic acid has unusual properties that enhance its potential as a new therapeutic agent. It is derived from human milk and thus is likely to be beneficial for breast-fed children. The protein used in this study was purified from milk that met the stringent criteria for feeding to premature babies. In a previous in vivo study of nude rats, xenotransplanted with human glioblastomas, no toxicity was observed,
16and we did not record any side effects on the skin of the treated patients. Other unusual features of this complex are its apoptosis-like mechanism of action and its apparent selectivity for tumor cells and immature cells. We conclude that α-lactalbumin–oleic acid has potential as a novel therapeutic tool in the treatment of papillomas and other tumors.
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