This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prostate cancer (PC) is the second leading cause of cancer deaths in men. The neuropeptide calcitonin (CT) and its receptor are exclusively localized in normal prostate epithelium and their expression is deregulated in malignant prostate. Exogenous CT raises tumorigenicity and metastatic potential of several PC cell lines. Disruption of cell-cell adhesion is a key mechanism associated with CT-stimulated prostate tumor growth and metastasis. Actin is a microfilament protein that forms versatile dynamic polymers, which can define cell polarity, control cell shape and promote stable cell-cell and cell-matrix adhesions. Overexpression of ABCB1/P-glycoprotein (P-gp) is one of the most common mechanisms for the development of multidrug resistance (MDR) in cancer cells. Phenylmethylene hydantoins (PMHs) are anti-metastatic leads discovered in our laboratory. PMHs augment cell-cell adhesion complexes, abolish proinvasive actions of CT, and attenuates CT-stimulated tumor growth and metastasis of PCs. The marine-derived macrolide latrunculins A and B are known to reversibly bind actin monomers, disrupting its polymerization. Rationally-designed analogs of latrunculin A were semisynthesized to modulate actin binding affinities and therefore showed potent anti-invasive activity at the nM level without cytotoxicity. Several novel sipholane triterpenoids were isolated from the sponge Callyspongia siphonella and were able to reverse P-gp-mediated multidrug resistance in human epidermoid cancer cells. Computer-assisted modeling methods like CoMFA, CoMSIA, and DISCOtech were used to establish and understand the structure-activity relationship, pharmacophore model, and guide the design of more potent analogs. PMHs, latrunculins, and sipholanes are potential anticancer leads.
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