Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action

Ponnusamy, Suriyan, Lattmann, Eric, Lattmann, Pornthip, Thiyagarajan, Thirumagal, Padinjarethalakal, Balaram N. and Narayanan, Ramesh (2016). Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action. Oncology Reports, 35 (4), pp. 2097-2106.

Abstract

Colon and pancreatic cancers contribute to 90,000 deaths each year in the USA. These cancers lack targeted therapeutics due to heterogeneity of the disease and multiple causative factors. One important factor that contributes to increased colon and pancreatic cancer risk is gastrin. Gastrin mediates its actions through two G-protein coupled receptors (GPCRs): cholecystokinin receptor A (CCK-A) and CCK-B/gastrin receptor. Previous studies have indicated that colon cancer predominantly expresses CCK-A and responds to CCK-A isoform antagonists. However, many CCK-A antagonists have failed in the clinic due to poor pharmacokinetic properties or lack of efficacy. In the present study, we synthesized a library of CCK-A isoform-selective antagonists and tested them in various colon and pancreatic cancer preclinical models. The lead CCK-A isoform, selective antagonist PNB-028, bound to CCK-A at 12 nM with a 60-fold selectivity towards CCK-A over CCK-B. Furthermore, it inhibited the proliferation of CCK-A-expressing colon and pancreatic cancer cells without affecting the proliferation of non-cancerous cells. PNB-028 was also extremely effective in inhibiting the growth of MAC-16 and LoVo colon cancer and MIA PaCa pancreatic cancer xenografts in immune-compromised mice. Genomewide microarray and kinase-array studies indicate that PNB-028 inhibited oncogenic kinases and angiogenic factors to inhibit the growth of colon cancer xenografts. Safety pharmacology and toxicology studies have indicated that PNB-028 is extremely safe and has a wide safety margin. These studies suggest that targeting CCK-A selectively renders promise to treat colon and pancreatic cancers and that PNB-028 could become the next-generation treatment option.

Publication DOI: https://doi.org/10.3892/or.2016.4588
Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences
Additional Information: Ponnusamy, S., Lattmann, E., Lattmann, P., Thiyagarajan, T., Padinjarethalakal, B.N., & Narayanan, R. (2016). Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action. Oncology Reports, 35, 2097-2106. https://doi.org/10.3892/or.2016.4588
Uncontrolled Keywords: CCK-A,CCK-B,cholecystokinin,colon cancer,G-protein coupled receptor,gastrin,kinases,pancreatic cancer,Cancer Research,Oncology
Full Text Link: http://www.span ... 92/or.2016.4588
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2016-04
Authors: Ponnusamy, Suriyan
Lattmann, Eric
Lattmann, Pornthip
Thiyagarajan, Thirumagal
Padinjarethalakal, Balaram N.
Narayanan, Ramesh

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