Lysophosphatidic acid type 2 receptor agonists in targeted drug development offer broad therapeutic potential

Abstract

The growth factor-like lipid mediator, lysophosphatidic acid (LPA), is a potent signaling molecule that influences numerous physiologic and pathologic processes. Manipulation of LPA signaling is of growing pharmacotherapeutic interest, especially because LPA resembles compounds with drug-like features. The action of LPA is mediated through activation of multiple types of molecular targets, including six G protein-coupled receptors that are clear targets for drug development. However, the LPA signaling has been linked to pathological responses that include promotion of fibrosis, atherogenesis, tumorigenesis, and metastasis. Thus, a question arises: Can we harness, in an LPA-like drug, the many beneficial activities of this lipid without eliciting its dreadful actions? We developed octadecyl thiophosphate (OTP; subsequently licensed as Rx100), an LPA mimic with higher stability in vivo than LPA. This article highlights progress made toward developing analogs like OTP and exploring prosurvival and regenerative LPA signaling. We determined that LPA prevents cell death triggered by various cellular stresses, including genotoxic stressors, and rescues cells condemned to apoptosis. LPA 2 agonists provide a new treatment option for secretory diarrhea and reduce gastric erosion caused by nonsteroidal anti-inflammatory drugs. The potential uses of LPA 2 agonists like OTP and sulfamoyl benzoic acid-based radioprotectins must be further explored for therapeutic uses.-Tigyi, G. J., L. R. acid type 2 receptor agonists in targeted drug development offer broad therapeutic potential. J. Lipid Res. 2019. 60: 464-474.Supplementary key words autotaxin • Rx100 • apoptosis • radiation mitigator • secretory diarrhea • gastric erosion • deoxyribonucleic acid damage repair

Lipid Phosphate Phosphatases and Cancer

“…By contrast, the knockout of LPAR1 or LPAR3 does not have this effect [ 168 ]. On the other hand, LPAR2 agonists show a therapeutic potential against irradiation-induced injury [ 168 , 169 ]. LPA contributes to the resistance of 786-O renal cancer cells to Temsirolimus and Sunitinib by activating Arf6 GTPase through LPAR2 [ 170 ].…”

Lysophosphatidic Acid and Autotaxin-associated Effects on the Initiation and Progression of Colorectal Cancer

“…LPA enhances cell survival post-irradiation, and the ability of LPA 2 to interact with TRIP6, Siva-1 or NHERF2 is critical in LPA-mediated protection of cells [158,163,165,166]. Lpar2 −/− mice have defects in intestinal epithelial recovery from radiation-induced injury, and LPA 2 agonists show a therapeutic potential against radiation-induced injury [167,168].…”

LPAR2 receptor activation attenuates radiation‐induced disruption of apical junctional complexes and mucosal barrier dysfunction in mouse colon

“…A significant body of evidence indicates that LPA plays a crucial role in the growth and differentiation of intestine as well as the protection of intestinal mucosa from a variety of noxious conditions 34,36,37,39,40 . The endogenous LPA and synthetic analogs such as RP‐1 protect the gut from the genotoxic stress‐triggered sequelae of pathophysiological events that underlie the acute gastrointestinal radiation syndrome 29 . However, the role of LPA in the protection of the colonic mucosal barrier function is poorly understood.…”

“…27 These actions led to a significant decrease in lethality after doses as high as 16 Gy. [12][13][14][15]18,28,29 The experimental groups for this study consisted of Sham (control), IR (vehicle), and IR+RP-1 (0.5 mg/ kg daily, s.c.). Vehicle or RP1 was administered at 0, 24, or 48 hours after irradiation.…”