Activation of lipoprotein lipase and inhibition of B16 melanoma-induced cachexia in mice by ponalrestat, an aldose reductase inhibitor.
Lipoprotein lipase (LPL) is a key regulatory enzyme responsible for the hydrolysis of triglyceride (TG)-rich lipoproteins. The reduction in LPL activity is observed in tumor bearing animals and cancer patients with cachectic symptoms, suggesting an involvement of LPL in inducing cancer cachexia. During a screening program for anti-cachectic agents we found that ponalrestat, an aldose reductase inhibitor, activates LPL activity. Ponalrestat increased the activity of LPL in adipose tissue in mice. The effect of ponalrestat on B16 melanoma-induced cachectic symptoms was next investigated in mice. The decrease in the weight of epididymal fat, carcass and whole body lipid was observed in mice following intraperitoneal inoculation of B16, compared to mice without the tumor inoculation. Treatment with ponalrestat resulted in the attenuation of the decrease in the tissue weight. The increase in the levels of TG and non-esterified fatty acid, and a decrease in the level of glucose in the blood, which was induced by the presence of tumor, were also restored to those of normal mice following ponalrestat treatment. The reduction in locomotor activity in tumor bearing mice was partially restored by the treatment with ponalrestat. Overall, this study demonstrated that ponalrestat, an aldose reductase inhibitor, possesses potent LPL activating activity and that the cachexia induced by B16 melanoma was alleviated by treatment with 'ponalrestat, suggesting that ponalrestat, a LPL activating agent, has a therapeutic potential for the treatment of cancer cachexia.
Kawamura
I
I
Pharmacological Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Yamamoto
N
N
Sakai
F
F
Yamazaki
H
H
Naoe
Y
Y
Inami
M
M
Manda
T
T
Shimomura
K
K
D016475:3T3 Cells; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002100:Cachexia / Q000517:prevention & control*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008055:Lipids / Q000032:analysis; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008297:Male; D008546:Melanoma, Experimental / Q000150:complications* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010793:Phthalazines / Q000494:pharmacology*; D011817:Rabbits
D004791:Enzyme Inhibitors; D008055:Lipids; D010793:Phthalazines; C042829:ponalrestat; D000449:Aldehyde Reductase; D008071:Lipoprotein Lipase