New role for the mitochondrial peptide humanin: protective agent against chemotherapy-induced side effects.

The remarkable advances made over the last several decades in the form of effective therapies that have substantially reduced the mortality from various malignancies, particularly those affecting pediatric patients, has presented the medical community with new challenges of dealing with cancer chemotherapy side effects. Cancer survivors, especially those who were treated for their cancer as children or adolescents, are frequently afflicted with various endocrinopathies, infertility, and growth impairment (1). Current adjuvant therapies that have been approved for dealing with chemotherapy side effects mainly address acute symptoms, such as nausea, and bone marrow renewal. There are multiple cancer drugs that cause damage to the growth plates of growing bones and currently can only be dealt with through later treatment with growth hormone and with variable results (2). The findings in the article by Eriksson and colleagues in this issue of the Journal (3) show that bortezomib-induced growth failure in mice was almost completely ameliorated by cotreatment with an analog of the mitochondrial-derived peptide humanin, while not interfering with the antitumor effects of bortezomib. Although not approved in children, bortezomib holds promise in childhood leukemia and other cancers affecting growing children, but among its most worrisome side effects in this population is the toxic effect on the growth plate. These investigators showed that a 2-week treatment with this recently approved proteasome inhibi-tor was quite effective in reducing the growth of neuroblastoma xenografts; however, it dramatically arrested bone growth in the host mice. Cotreatment with intraperitoneal injections of a huma-nin analog twice a week reversed the growth arrest but maintained the tumor-inhibitory effect of bortezomib. The effects of humanin on tibia growth occurred, at least in part, by protecting the cells in the growth plate from bortezomib toxicity. This phenomenon is reminiscent of the concept of differential protection, whereby an intervention protects from the toxic effects of chemotherapy on healthy host organs while enhancing its killing effects on cancer cells, which was first proposed by Longo and colleagues using fasting (4). Mitochondria are central to multiple biological processes, including energy metabolism, apoptosis, and the integration of oxidative stress (5), and mitochondrial dysfunction is a hallmark of aging and multiple aging-related diseases from diabetes to dementia. The mitochondrial peptide humanin was discovered more than a decade ago nearly simultaneously by three different groups who cloned an open-reading frame from the mitochon-drial 16S rRNA region encoding a 24-aminoacid peptide with potent neuroprotective (6), antiapoptotic (7), …