Description
Prostate cancer (PCa) is the most common cancer among men and is the second leading cause of cancer-related deaths in males in the United States and Europe. PCa is more common in African-American than Caucasian-American men, potentially because African-American men have a higher expression of androgen receptors. Early treatments include deprivation of androgen and removal of prostate tissues. However, these treatments may be rendered ineffective as the disease progresses to become androgen-independent (the castrate refractory stage) and as the tumor metastasizes. Finding additional and more effective treatments for castrate refractory PCa is highly desirable. Our lab has previously identified peptides that stabilize Holliday junctions (HJs) formed during DNA recombination reactions by inhibiting their resolution. HJs are intermediates in homologous recombination repair (HRR) pathway and cancer cells depend more on HRR than normal cells as they have uncontrolled replication and proliferation. Our most potent peptide, wrwycr, is active as a homodimer. In order to increase the potential of developing chemotherapeutic agents targeting DNA repair, we identified non-peptide small molecule surrogates from over 20 different chemical scaffolds; two types of scaffolds yielded small molecules (1609-3, 1609-10, 1795-3 and 1795-10) that shared some properties with the peptides, including interactions with HJs. Results of cell viability and cytotoxicity assays have shown that all of the 1609 and 1795 compounds caused cell death in PC3 cells, and that one of the molecules reduces total DNA synthesis, but not total RNA or protein synthesis. Small molecule-induced cell death is lethal and independent of p53-induced apoptosis. In addition, small molecules induce double-stranded DNA breaks, as evident from the activation of DNA damage sensors, _H2AX and p53-binding protein 1 (53BP1). As expected, the downstream signaling checkpoint proteins, Chk1 and Chk2 are activated in consequence. However, no cell cycle arrest was observed. However, contrary to our hypothesis that the small molecules may interfere with double strand break repair, there was no synergy between compound 1795-10 and ionizing radiation.
