Using genotoxic agents to destroy tumor cells has been for decades a standard therapeutic approach for treating many cancers. Chemotherapies that cause DNA damage, inhibit DNA repair, promote mitotic catastrophe or induce apoptosis are effective against proliferating tumor cells. Because they are delivered systemically and not specifically targeted to tumors, however, such treatments often kill normal cells and produce harsh side effects in treated patients. Continuously proliferating bone marrow stem cells and spermatogonial stem cells, in particular, are vulnerable to traditional chemotherapies, and their death can lead to secondary immunodeficiencies and infertility. In a new study published in Endocrinology, a research team led by Dr. Christina Wang at the University of California, Los Angeles demonstrates that using a humanin analogue, HNG, as an adjuvant to include with chemotherapeutic strategies protects susceptible normal cells from damage. Humanin is a mitochondrially-encoded, small circulating micropeptide for which neuroprotective and anti-apoptotic properties have been observed in some tissue types. In the study, chemotherapies that included HNG protected leucocytes and male germ cells from cell death and, surprisingly, reduced metastases in the researchers’ cancer model. The data suggests that including HNG as an adjuvant in tumor-targeting regimens may decrease the severity of chemotherapy-associated side effects in many patients.
To test their potential protective agent, HNG, in a cancer treatment scenario, Dr. Wang’s team used a mouse syngeneic tumor model in which C57BL/6J (000664) male mice were injected via the tail vein with the C57BL/6-derived B16 melanoma cell line. The melanoma cells established metastatic lung lesions which were then assessed following experimental interventions. The reference chemotherapy compound the UCLA investigators utilized was cyclophosphamide (CP), a DNA alkylating agent that induces cell death by generating DNA crosslinks that the cell cannot repair. In murine melanoma models, CP suppresses lung metastases, decreases peripheral leukocyte numbers, and inhibits spermatogenesis.
Co-treatment of engrafted mice with CP and HNG significantly reduced the number of lung metastases observed compared to mice that were treated with CP alone (approximately 60 versus 110 metastatic tumors were observed in the two cohorts, respectively; untreated animals had close to 150), although the overall size of the lesions were quite similar between the two treatment groups. CP treatment also reduced significantly the percentages of white blood cells (~60%), granulocytes (~75%), monocytes (~50%), and lymphocytes (~66%) circulating in the animals’ peripheral blood. Mice that received HNG with CP showed white blood cell, granulocyte, and monocyte levels near or higher than untreated animals, but overall lymphocyte numbers were not recovered by including HNG with CP. The observed rescue of immune cells in the HNG+CP treated mice suggests that improved immune activity is likely to result in recipients as well. To determine if HNG can also protect spermatogonial cells from CP-induced apoptosis, the investigators used TUNEL staining to examine apoptotic cell numbers in histological sections from the testes of treated animals and also measured the animals’ sperm counts. Animals co-treated with HNG and CP had fewer TUNEL-positive apoptotic cells and improved sperm counts compared to males treated with CP alone.
These data suggest that adjuvant therapy with HNG may protect vulnerable, normal cell types from chemotherapeutic-mediated damage. For many cancer patients such adjuvant combination therapies may improve their quality of life until more tumor cell-targeted therapies are developed.