title: The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice.
abstract: Humanin is a peptide that is cytoprotective against stresses in many cell types. We investigated whether a potent humanin analogue S14G-humanin (HNG) would protect against chemotherapy-induced damage to normal cells without interfering with the chemotherapy-induced suppression of cancer cells. Young adult male mice were inoculated iv with murine melanoma cells. After 1 week, cancer-bearing mice were randomized to receive either: no treatment, daily ip injection of HNG, a single ip injection of cyclophosphamide (CP), or CP+HNG and killed at the end of 3 weeks. HNG rescued the CP-induced suppression of leucocytes and protected germ cell from CP-induced apoptosis. Lung metastases were suppressed by HNG or CP alone, and further suppressed by CP+HNG treatment. Plasma IGF-1 levels were suppressed by HNG with or without CP treatment. To investigate whether HNG maintains its protective effects on spermatogonial stem cells, sperm output, and peripheral leucocytes after repeated doses of CP, normal adult male mice received: no treatment, daily sc injection of HNG, 6 ip injections of CP at 5-day intervals, and the same regimens of CP+HNG and killed at the end of 4 weeks of treatment. Cauda epididymal sperm counts were elevated by HNG and suppressed by CP. HNG rescued the CP-induced suppression of spermatogonial stem cells, sperm count and peripheral leucocytes. We conclude that HNG 1) protects CP-induced loss of male germ cells and leucocytes, 2) enhances CP-induced suppression of cancer metastases, and 3) acts as a caloric-restriction mimetic by suppressing IGF-1 levels. Our findings suggest that humanin analogues may be promising adjuvants to chemotherapy.
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: YanHe
authors.initials: Y
authors.lastname: Lue
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: Ronald
authors.initials: R
authors.lastname: Swerdloff
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: Junxiang
authors.initials: J
authors.lastname: Wan
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: Jialin
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: Samuel
authors.initials: S
authors.lastname: French
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: Vince
authors.initials: V
authors.lastname: Atienza
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: Victor
authors.initials: V
authors.lastname: Canela
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Bruhn
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: Brian
authors.initials: B
authors.lastname: Stone
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: Yue
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: Pinchas
authors.initials: P
authors.lastname: Cohen
authors.affiliation: Division of Endocrinology (Y.L., R.S., V.A., V.C., B.S., Y.J., C.W.) and Division of Dermatology (K.V.B.), Department of Medicine, Harbor-University of California, Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502; University of Southern California Davis School of Gerontology (J.W., J.X., P.C.), University of Southern California, Los Angeles, California 90033; and Department of Pathology (S.F.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90502.
authors.forename: Christina
authors.initials: C
authors.lastname: Wang
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003520:Cyclophosphamide / Q000494:pharmacology*; D005854:Germ Cells / Q000187:drug effects; D007274:Injections, Intraperitoneal; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000187:drug effects / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D009368:Neoplasm Transplantation; D010455:Peptides / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D011897:Random Allocation; D013076:Sperm Count; D013094:Spermatozoa / Q000187:drug effects*
chemical_list: D018906:Antineoplastic Agents, Alkylating; C450880:Gly(14)-Humanin; D018970:Insulin-Like Growth Factor Binding Protein 1; D010455:Peptides; D020011:Protective Agents; D007334:Insulin-Like Growth Factor I; D003520:Cyclophosphamide