CI-988 Inhibits EGFR Transactivation and Proliferation Caused by Addition of CCK/Gastrin to Lung Cancer Cells

Moody, Terry W.; Nuche-Berenguer, Bernardo; Moreno, Paola; Jensen, Robert T.

doi:10.1007/s12031-015-0533-6

Cited by 14 publications

(15 citation statements)

References 43 publications

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“…The EGFR activates the Ras, Raf, MEK and ERK pathway resulting in altered cellular proliferation. The increase in EGFR and ERK tyrosine phosphorylation caused by addition of CCK-8 to lung carcinoid NCI-H727 cells was significantly inhibited by CI-988, PP2, gefitinib and GM6001, a MMP inhibitor 93 . In gastric epithelial cells, gastrin increases MMP9 expression 94 .…”

Section: Cck Receptors and Other Cancersmentioning

confidence: 94%

The Role of Gastrin and CCK Receptors in Pancreatic Cancer and other Malignancies

Smith¹,

Fonkoua²,

Moody³

2016

Int. J. Biol. Sci.

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The gastrointestinal (GI) peptide gastrin is an important regulator of the release of gastric acid from the stomach parietal cells and it also plays an important role in growth of the gastrointestinal tract. It has become apparent that gastrin and its related peptide cholecystokinin (CCK) are also significantly involved with growth of GI cancers as well as other malignancies through activation of the cholecystokinin-B (CCK-B) receptor. Of interest, gastrin is expressed in the embryologic pancreas but not in the adult pancreas; however, gastrin becomes re-expressed in pancreatic cancer where it stimulates growth of this malignancy by an autocrine mechanism. Strategies to down-regulate gastrin or interfere with its interface with the CCK receptor with selective antibodies or receptor antagonists hold promise for the treatment of pancreatic cancer and other gastrin - responsive tumors.

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Section: Cck Receptors and Other Cancersmentioning

confidence: 94%

The Role of Gastrin and CCK Receptors in Pancreatic Cancer and other Malignancies

Smith¹,

Fonkoua²,

Moody³

2016

Int. J. Biol. Sci.

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“…Lung cancer is associated with overexpression of CCK 2 receptors. 34 NCI-H322 was derived in 1981 from a primary bronchioalveolar carcinoma of the lung from a 52 year old male. Cells of this non-small cell carcinoma cell line produce tumours in athymic mice.…”

Section: Cell Based In Vitro Assaymentioning

confidence: 99%

N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer

Lattmann

Russell

Singh

et al. 2018

MOJDDT

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Background: Cholecystokinin and gastrin are endocrine growths factors for certain tumours and CCK 1 R and CCK2R receptors are ideal molecular targets for novel smart chemotherapeutics with a beneficial overall profile due to their anxiolytic and antidepressant properties. Lung cancers are fuelled by gastrin and therefore, selective gastrin (CCK 2 R) antagonists are ideal experimental drug candidates. Objective: Synthesis and evaluation of novel CCK antagonists, most preferred CCK 2 / gastrin selective for the treatment of lung cancers. Methods: A fast and efficient synthesis of hydroxy-pyrrolones in 2 steps from renewable biomass was performed. After initial radiolabelled receptor binding studies with hot CCK8, subsequent in vitro evaluation with isolated duodenum preparations confirmed CCK antagonism. Cell based studies using the MTT assay provided a candidate for in vivo xenograft models with nude mice. Rational drug design was supported by molecular modelling experiments. Results: Potent and selective CCK antagonists were prepared as stable crystalline materials in high yields. Gastrin antagonists were in vitro active on isolated tissue preparations and inhibited breast, colon and lung cancer cell lines in vitro with IC 50 to 45nM for the privileged hydroxyl-pyrrolone lead structure in the MTT assay for human cancer cell lines. PNB-101, a fluorinated 5-hydroxy-5-aryl-pyrrol-2-one, gave up to 80% inhibition of tumour growths by oral administration in athymic mice transplanted with the human lung cancer cell line H727. Conclusion: PNB-101 is a potential chemotherapeutic agent for CCK-gastrin related cancers and entered preclinical development.

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“…Cancer cells produce and secrete the neuropeptides CCK/gastrin [ 34 , 129 ], GRP and NMB [ 130 , 131 ], bradykinin [ 132 ], and vasopressin [ 133 , 134 ]. A plethora of evidence exists elucidating the autocrine growth and pro-proliferative effects exerted by CCK/gastrin [ 135 , 136 ], GRP and NMB [ 137 , 138 ], bradykinin [ 139 , 140 ] and vasopressin [ 21 , 94 , 95 , 141 , 142 ] through their respective receptors. In the process, they increase the colony number of cancer cells, including lung cancer [ 21 , 135 , 143 ].…”

Section: Introductionmentioning

confidence: 99%

“…A plethora of evidence exists elucidating the autocrine growth and pro-proliferative effects exerted by CCK/gastrin [ 135 , 136 ], GRP and NMB [ 137 , 138 ], bradykinin [ 139 , 140 ] and vasopressin [ 21 , 94 , 95 , 141 , 142 ] through their respective receptors. In the process, they increase the colony number of cancer cells, including lung cancer [ 21 , 135 , 143 ]. Weber et al reported that even activation of orphan receptor BRS-3 may contribute to cancer cell proliferation, since the analogue [d-Phe 6 , β-Ala 11 , Phe 13 , Nle 14 ] bombesin (6–14) caused enhanced nuclear oncogene expression, MAPK phosphorylation, and Elk-1 activation in lung cancer cells [ 144 ].…”

Section: Introductionmentioning

confidence: 99%

“…Weber et al reported that even activation of orphan receptor BRS-3 may contribute to cancer cell proliferation, since the analogue [d-Phe 6 , β-Ala 11 , Phe 13 , Nle 14 ] bombesin (6–14) caused enhanced nuclear oncogene expression, MAPK phosphorylation, and Elk-1 activation in lung cancer cells [ 144 ]. Research has indicated that GPCR transactivation of epidermal growth factor receptor (EGFR) is significantly involved in cancer cell proliferation [ 135 , 145 ]. For instance, the BRS-3 agonist (DTyr 6 , βAla 11 , Phe 13 , Nle 14 )bombesin 6–14 (BA1) caused Tyr 1068 phosphorylation of EGFR in NCI-H727 or NCI-H1299 cells stably transfected with BRS-3 (NCI-H1299-BRS-3), and significantly increased the clonal growth of NCI-H1299-BRS-3 cells.…”

Section: Introductionmentioning

confidence: 99%

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Exploiting cancer’s phenotypic guise against itself: targeting ectopically expressed peptide G-protein coupled receptors for lung cancer therapy

et al. 2017

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Lung cancer, claiming millions of lives annually, has the highest mortality rate worldwide. This advocates the development of novel cancer therapies that are highly toxic for cancer cells but negligibly toxic for healthy cells. One of the effective treatments is targeting overexpressed surface receptors of cancer cells with receptor-specific drugs. The receptors-in-focus in the current review are the G-protein coupled receptors (GPCRs), which are often overexpressed in various types of tumors. The peptide subfamily of GPCRs is the pivot of the current article owing to the high affinity and specificity to and of their cognate peptide ligands, and the proven efficacy of peptide-based therapeutics. The article summarizes various ectopically expressed peptide GPCRs in lung cancer, namely, Cholecystokinin-B/Gastrin receptor, the Bombesin receptor family, Bradykinin B1 and B2 receptors, Arginine vasopressin receptors 1a, 1b and 2, and the Somatostatin receptor type 2. The autocrine growth and pro-proliferative pathways they mediate, and the distinct tumor-inhibitory effects of somatostatin receptors are then discussed. The next section covers how these pathways may be influenced or ‘corrected’ through therapeutics (involving agonists and antagonists) targeting the overexpressed peptide GPCRs. The review proceeds on to Nano-scaled delivery platforms, which enclose chemotherapeutic agents and are decorated with peptide ligands on their external surface, as an effective means of targeting cancer cells. We conclude that targeting these overexpressed peptide GPCRs is potentially evolving as a highly promising form of lung cancer therapy.

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CI-988 Inhibits EGFR Transactivation and Proliferation Caused by Addition of CCK/Gastrin to Lung Cancer Cells

Cited by 14 publications

References 43 publications

The Role of Gastrin and CCK Receptors in Pancreatic Cancer and other Malignancies

The Role of Gastrin and CCK Receptors in Pancreatic Cancer and other Malignancies

N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer

Exploiting cancer’s phenotypic guise against itself: targeting ectopically expressed peptide G-protein coupled receptors for lung cancer therapy

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