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  • We have previously established the pharmacokinetic profile

    2022-05-13

    We have previously established the pharmacokinetic profile and effective dose of MNF in the rat [43] and demonstrated the effectiveness of MNF as an anticancer drug in Protionamide sale and xenograft models [44]. Moreover, MNF was found to effectively block GPR55 signaling in tumor cells [21]. The compound CID inhibits agonist-induced Ca2+ signaling and ERK1/2 phosphorylation in HEK cells overexpressing GPR55, and blocks GPR55-mediated activation and nuclear translocation of NFAT and NF-κB transcription factors in these cells [45]. More recently, CID was reported to reduce tumorigenic properties of ovarian and colon cancer cell lines and in in vivo tumor models [23], [46]. These results indicate that both MNF and CID have the potential to become effective therapeutic agents against cancers where GPR55 plays a significant role. Since PANC-1 cells are widely used in the development of pancreatic cancer therapies, the data from this study suggest that GPR55 antagonism represent a promising new approach to the treatment of pancreatic cancer. We are currently exploring the extent of this effect across multiple pancreatic cancer cell lines and patient-derived xenograft models and the results will be published elsewhere. In conclusion, GPR55 antagonists offer a rational therapeutic approach to reversing the MDR phenotype. On the basis of our findings, we provide a bimodal model for the activity of GPR55 antagonists in PancCa cells (Fig. 7), which appears to also be applicable to other GPR55-expressing tumors. In this model, GPR55 antagonism attenuates both the constitutive and ligand-inducible activity of the MEK/ERK and PI3K/AKT pathways, which results in reduced phosphorylation and nuclear translocation of PKM2 and concomitant decrease in HIF-1α and β-catenin levels. This, in turn, significantly downregulates MDR protein expression and disrupts feed-forward loops responsible for chemoresistance and survival in tumor cells.
    Disclosure of potential conflicts of interest Drs. Bernier and Wainer are listed as co-inventors on an issued patent for (R,R⿿)-MNF and other fenoterol derivatives and in submitted patents for their use in glioblastomas and astrocytomas. Drs. Bernier and Wainer have assigned their rights in the patents to the US government, but will receive a percentage of any royalties that may be received by the government. Dr. Wainer is currently Chief Scientific Officer of Mitchell Woods Pharmaceuticals, which has an exclusive license for the use of (R,R⿿)-MNF and related compounds in the treatment of pancreatic, liver and brain cancers. The remaining author states no conflict of interest.
    Authorship contributions Participated in research design: Singh, Bernier, Wainer Conducted experiments and data acquisition: Singh, Performed data analysis and interpretation: Singh, Bernier, Wainer Wrote or contributed to the writing of the manuscript: Singh, Bernier, Wainer Study supervision: Bernier, Wainer.
    Acknowledgments This work was supported by funds from the Intramural Research Program of the National Institute on Aging at NIH. This paper is subject to the NIH Public Access Policy.
    Introduction LPI was first identified in the early 1960s (Keenan and Hokin, 1962) and very little was known about its physiological functions. It was not until 20 years later that a potential signalling role was suggested, when it was shown that LPI can stimulate the release of insulin from pancreatic β-cells (Metz, 1986). The first evidence of a role for LPI in cancer was provided in 1994 by our group in a study demonstrating that LPI levels were highly elevated in thyroid cells overexpressing Ras (Falasca and Corda, 1994). In the latter study, LPI has also been identified as a mitogenic factor in these cells. Subsequently, we unraveled the signalling pathways activated by LPI in cancer cells and the ability of Ras-transformed fibroblasts to secrete LPI (Falasca et al., 1995, Falasca et al., 1998). In 2000, clinical data supported a role for LPI in cancer progression. Indeed, Xiao et al. found that the levels of LPI were elevated in patients with ovarian cancer, as assessed by electrospray ionization mass spectrometry (Xiao et al., 2000). These data were then confirmed in 2004, when Sutphen et al. demonstrated that LPI, together with other lysophospholipids, could be a useful biomarker in ovarian cancer (Sutphen et al., 2004). Lysophospholipids are well known lipid mediators that exert their functions through the activation of G protein-coupled receptors (GPCR) specific to each lysophospholipid. While the roles of lysophospholipids such as lysophosphatidic acid and sphingosine 1-phosphate (Hausmann et al., 2013, Nagahashi et al., 2014) are well established, relatively little is known about LPI functions. The major limitation in LPI research was the fact that its receptor was not identified until 2007, when a study demonstrated that LPI induces ERK1/2 phosphorylation through activation of the GPCR GPR55 (Oka et al., 2007). The finding of a LPI specific receptor has opened up new and diversified avenues for the lipid mediator research.