Exploitation of the derivatives of Dictyostelium differentiation-inducing factor-1, which promote glucose consumption in mammalian cells.
OBJECTIVE
The differentiation-inducing factor-1 (DIF-1) is a signal molecule that induces stalk cell formation in the cellular slime mold Dictyostelium discoideum. DIF-1 has also been shown to possess pharmacological activities, such as the suppression of tumor cell growth and the promotion of glucose uptake in non-transformed mammalian cells. In this study, we tried to develop compounds that possess weaker anti-tumor activity and stronger glucose uptake-promoting activity than DIF-1.


METHODS
We investigated the in vitro effects of 12 derivatives of DIF-1 on glucose consumption in mouse 3T3-L1 cells and on cell growth in K562 human leukemia cells. We also examined the effect of a good compound on the blood glucose concentration in KK-Ay diabetic mice.


RESULTS
We found that some derivatives at 20 microM promoted glucose consumption more than twice as fast as the control. Of the derivatives, a compound named DIF-1(3M), which has a weaker anti-leukemic effect than DIF-1, promoted glucose consumption as strongly as DIF-1 in confluent 3T3-L1 cells. While DIF-1 at 20 microM was inhibitory to the cell growth of 3T3-L1, DIF-1(3M) at 20 microM exhibited no inhibitory effect on the growing cells. We also found that DIF-1(3M) injected (10-12.5 mg/kg body weight) intraperitoneally in mice tended to lower the blood glucose concentration.


CONCLUSIONS
The present results open the possibility for the development of new agents that possess strong glucose-uptake-promoting activity but little anti-tumor activity and may have therapeutic potential for the treatment of diabetes and/or obesity.
Kubohara
Yuzuru
Y
Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi 371-8512, Japan. kubohara@showa.gunma-u.ac.jp
Kikuchi
Haruhisa
H
Oshima
Yoshiteru
Y
D041721:3T3-L1 Cells; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005947:Glucose / Q000378:metabolism*; D006588:Hexanones / Q000494:pharmacology*; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000494:pharmacology*; D020014:K562 Cells; D008297:Male; D051379:Mice
D001786:Blood Glucose; C490570:Differentiation-inducing factor-1, Dictyostelium; D006588:Hexanones; D006843:Hydrocarbons, Chlorinated; D005947:Glucose; D002118:Calcium