Targeting melanoma growth and viability reveals dualistic functionality of the phosphonothionate analogue of carba cyclic phosphatidic acid.
BACKGROUND
Although the incidence of melanoma in the U.S. is rising faster than any other cancer, the FDA-approved chemotherapies lack efficacy for advanced disease, which results in poor overall survival. Lysophosphatidic acid (LPA), autotaxin (ATX), the enzyme that produces LPA, and the LPA receptors represent an emerging group of therapeutic targets in cancer, although it is not known which of these is most effective.


RESULTS
Herein we demonstrate that thio-ccPA 18:1, a stabilized phosphonothionate analogue of carba cyclic phosphatidic acid, ATX inhibitor and LPA1/3 receptor antagonist, induced a marked reduction in the viability of B16F10 metastatic melanoma cells compared with PBS-treated control by 80-100%. Exogenous LPA 18:1 or D-sn-1-O-oleoyl-2-O-methylglyceryl-3-phosphothioate did not reverse the effect of thio-ccPA 18:1. The reduction in viability mediated by thio-ccPA 18:1 was also observed in A375 and MeWo melanoma cell lines, suggesting that the effects are generalizable. Interestingly, siRNA to LPA3 (siLPA3) but not other LPA receptors recapitulated the effects of thio-ccPA 18:1 on viability, suggesting that inhibition of the LPA3 receptor is an important dualistic function of the compound. In addition, siLPA3 reduced proliferation, plasma membrane integrity and altered morphology of A375 cells. Another experimental compound designed to antagonize the LPA1/3 receptors significantly reduced viability in MeWo cells, which predominantly express the LPA3 receptor.


CONCLUSIONS
Thus the ability of thio-ccPA 18:1 to inhibit the LPA3 receptor and ATX are key to its molecular mechanism, particularly in melanoma cells that predominantly express the LPA3 receptor. These observations necessitate further exploration and exploitation of these targets in melanoma.
Altman
Molly K
MK
Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, Athens, Georgia 30602, USA.
Gopal
Vashisht
V
Jia
Wei
W
Yu
Shuangxing
S
Hall
Hassan
H
Mills
Gordon B
GB
McGinnis
A Cary
AC
Bartlett
Michael G
MG
Jiang
Guowei
G
Madan
Damian
D
Prestwich
Glenn D
GD
Xu
Yong
Y
Davies
Michael A
MA
Murph
Mandi M
MM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010712:Phosphatidic Acids / Q000494:pharmacology*; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000099189:Lysophospholipase D
D000970:Antineoplastic Agents; D009097:Multienzyme Complexes; D010712:Phosphatidic Acids; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D