Dietary dehydroepiandrosterone inhibits bone marrow and leukemia cell transplants: role of food restriction.
Dietary dehydroepiandrosterone (DHEA) inhibits the proliferation of syngeneic bone marrow cells (BMC) infused into lethally irradiated mice. Potential mechanisms for suppression of hematopoiesis were evaluated and the findings were as follows: (i) depletion of NK, T, B or macrophage cells failed to reverse suppression by DHEA; (ii) stem cell stimulation by erythropoietin, growth hormone, interleukin-2, Friend leukemia virus, or cyclophosphamide failed to reverse suppression; (iii) supplementation of fatty acids, mevalonate, or deoxyribonucleotides, which are dependent upon glucose-6-phosphate dehydrogenase function, did not enhance BMC growth in mice fed DHEA; (iv) DHEA downstream metabolites 4-androstenedione and 17beta-estradiol, as well as the synthetic steroid, 16alpha-chloroepiandrosterone (but not testosterone or 5-androstene-3beta,17beta-diol), also inhibited BMC growth. Tamoxifen antagonized the effects of 17beta-estradiol but not DHEA; (v) dietary DHEA causes hypothermia, but housing of DHEA-fed mice at 34 degrees C to maintain normal body temperature did not reverse suppression; (vi) DHEA leads to a decrease in food intake in rodents. Pair-feeding control diet to mice fed DHEA mimicked the effects of dietary DHEA; (vii) adrenalectomy and orchiectomy decrease the levels of stress and sex hormones, respectively. Neither procedure affected the ability of food restriction or DHEA feeding to inhibit hematopoiesis; (viii) growth of GR-3 NM pre-B leukemia cells in unirradiated mice was also suppressed by DHEA or food restriction. We conclude that DHEA, by reducing food intake in mice, inhibits bone marrow and leukemia cell growth. The precise mechanism(s) by which reduced food intake per se inhibits hematopoiesis is not known, but may involve an increased rate of cellular apoptosis.
Catalina
Fernando
F
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9072, USA.
Milewich
Leon
L
Kumar
Vinay
V
Bennett
Michael
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D016026:Bone Marrow Transplantation / Q000276:immunology; D003165:Complement System Proteins / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000378:metabolism / Q000494:pharmacology*; D004032:Diet; D005260:Female; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007942:Leukemia, Experimental / Q000178:diet therapy / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000276:immunology; D013256:Steroids / Q000502:physiology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D007166:Immunosuppressive Agents; D013256:Steroids; D003687:Dehydroepiandrosterone; D003165:Complement System Proteins; D005954:Glucosephosphate Dehydrogenase