Identification of a small molecule class to enhance cell-cell adhesion and attenuate prostate tumor growth and metastasis

Abstract

Expression of calcitonin (CT) and its receptor (CTR) is elevated in advanced prostate cancer, and activated CT-CTR autocrine axis plays a pivotal role in tumorigenicity and metastatic potential of multiple prostate cancer cell lines. Recent studies suggest that CT promotes prostate cancer metastasis by reducing cell-cell adhesion through the disassembly of tight and adherens junctions and activation of B-catenin signaling. We attempted to identify a class of molecules that enhances cell-cell adhesion of prostate cells and reverses the disruptive actions of CT on tight and adherens junctions. Screening several compounds led to the emergence of phenyl-methylene hydantoin (PMH) as a lead candidate that can augment cell-cell adhesion and abolish disruptive actions of CT on junctional complexes. PMH reduced invasiveness of PC-3M cells and abolished proinvasive actions of CT. Importantly, PMH did not display significant cytotoxicity on PC-3M cells at the tested doses. I.p. administered PMH and its S-ethyl derivative remarkably decreased orthotopic tumor growth and inhibited the formation of tumor micrometastases in distant organs of nude mice. PMH treatment also reduced the growth of spontaneous tumors in LPB-Tag mice to a significant extent without any obvious cytotoxic effects. By virtue of its ability to stabilize cell junctions, PMH could reverse the effect of CT on junctional disruption and metastasis, which strengthens the possibility of using PMH as a potential drug candidate for CT-positive androgen-independent prostate cancers.

Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products

“…9 The natural PMH 1 and the synthetic 4 showed potent in vitro anti-growth and anti-invasive properties against PC-3M prostate cancer cells in MTT and spheroid disaggregation assays. 10 PMH 1 and 4 also showed anti-invasive activity in orthotopic xenograft of PC-3M cells in nude mice model. 10 They decreased orthotopic tumor growth and inhibited the formation of tumor micrometastases in distant organs without apparent cytotoxic effects at the test doses.…”

“…10 PMH 1 and 4 also showed anti-invasive activity in orthotopic xenograft of PC-3M cells in nude mice model. 10 They decreased orthotopic tumor growth and inhibited the formation of tumor micrometastases in distant organs without apparent cytotoxic effects at the test doses. 10 PMH 4 also showed potent activity in LPB-Tag mice transgenic model.…”

“…10 PMH 4 also showed potent activity in LPB-Tag mice transgenic model. 10 Prostate tumors of LPB-Tag mice display significant similarities with human tumors including tumor heterogeneity, neuroendocrine features and relatively slower tumor growth. 10 PMH 4 remarkably reduced growth of primary tumors and their metastasis in reproductive organs, decreased morbidity and increased survival of the LPB-Tag mice.…”

“…10 They decreased orthotopic tumor growth and inhibited the formation of tumor micrometastases in distant organs without apparent cytotoxic effects at the test doses. 10 PMH 4 also showed potent activity in LPB-Tag mice transgenic model. 10 Prostate tumors of LPB-Tag mice display significant similarities with human tumors including tumor heterogeneity, neuroendocrine features and relatively slower tumor growth.…”

“…10 Prostate tumors of LPB-Tag mice display significant similarities with human tumors including tumor heterogeneity, neuroendocrine features and relatively slower tumor growth. 10 PMH 4 remarkably reduced growth of primary tumors and their metastasis in reproductive organs, decreased morbidity and increased survival of the LPB-Tag mice. Therefore, PMH 1 and 4 were suggested as potent attenuators of the disassembly of junctional complexes which are key events in the progression of a localized prostate tumor to its metastatic form.…”