Identification of a small molecule class to enhance cell-cell adhesion and attenuate prostate tumor growth and metastasis.
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 beta-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.
Shah
Girish V
GV
Department of Pharmaceutical Sciences, University of Louisiana College of Pharmacy, 1800 Bienville Drive, Monroe, LA 71209, USA. shah@ulm.edu
Muralidharan
Anbalagan
A
Thomas
Shibu
S
Gokulgandhi
Mitan
M
Mudit
Mudit
M
Khanfar
Mohammad
M
El Sayed
Khalid
K
D000818:Animals; D000970:Antineoplastic Agents / Q000145:classification / Q000302:isolation & purification* / Q000494:pharmacology* / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000473:pathology*; D054852:Small Molecule Libraries / Q000032:analysis / Q000145:classification; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D006827:Hydantoins; D054852:Small Molecule Libraries