Dehydroepiandrosterone-sulfate inhibits pancreatic carcinoma cell proliferation in vitro and in vivo.
BACKGROUND
Dehydroepiandrosterone-sulfate (DHEA-S) is a potent inhibitor of glucose-6 phosphate dehydrogenase, the rate limiting enzyme of the hexose monophosphate shunt, a biochemical pathway that provides substrate for DNA synthesis in neoplastic tissue. DHEA-S has been shown to inhibit the growth of neoplasms arriving from human skin, lung, colon, and mammary tissue. This study evaluates the effect of DHEA-S on human pancreatic cancer cell lines in vitro and in vivo.


METHODS
In vitro, the human pancreatic adenocarcinoma cell lines MiaPaCa-2, Capan-1, Capan-2, CAV and Panc-1 were treated with concentrations of 1.9 mumol/L to 1000 mumol/L DHEA-S in 1% dimethylsulfoxide (DMSO) for 5 consecutive days. Cell proliferation was determined by a nonradioactive cell proliferation assay and compared with DMSO treated controls. In vivo testing was performed by inoculating two cell lines, MiaPaCa-2 and Panc-I, into the flank of 40 male nude athymic mice in four study groups. After 1 week of growth, 667 mg/kg DHEA-S in 1% DMSO or 0.2 ml 1% DMSO alone in the control group was administered by daily intraperitoneal injection. Body weight and tumor size was recorded weekly, and tumor weight was measured after 3 weeks of treatment.


RESULTS
In vitro cell proliferation was decreased in the five cell lines by 36% to 62% of controls (p < 0.001) at 500 mumol/L DHEA-S. In vivo, after 2 weeks, tumor size was only 76% (p < 0.008) and 67% (p < 0.005) of the controls. After 3 weeks of treatment, tumor size was 73% (p < 0.001) and 53% (p < 0.001) of controls, and tumor weight was decreased by 73% in MiaPaCa-2 (p < 0.001) and 66% in Panc-1 (p < 0.001). Radioimmunoassay measurements of DHEA-S and testosterone from DHEA-S treated mouse plasma showed a significant increase in circulating levels of these hormones.


CONCLUSIONS
DHEA-S achieves high serum levels after intraperitoneal injection without elevation of serum testosterone levels and produces no significant toxicity. Treatment with DHEA-S results in a significant reduction of proliferation of human pancreatic cancer cells in culture and when grown as subcutaneous tumors in athymic nude mice.
Melvin
W S
WS
Division of General Surgery, Ohio State University, Columbus, USA.
Boros
L G
LG
Muscarella
P
P
Brandes
J L
JL
Johnson
J A
JA
Fisher
W E
WE
Schirmer
W J
WJ
Ellison
E C
EC
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D019314:Dehydroepiandrosterone Sulfate