| Cancer is a heterogeneous disease and can be characterized as the growth of a malignant cell population that eventually leads to the interference of normal physiological functions. Anticancer drug research focuses on inhibition of tumor cell growth and induction of apoptosis (programmed cell death) in the malignant cell population. Activation of the apoptotic program in tumorigenic cells is essential for cancer prevention and treatment. Reported in this dissertation are three approaches to targeting molecular differences found in tumor cells. Inhibition of the IL-2Ralpha signaling pathway, proteasome catalytic activity, or proliferative potential leads to a selective induction of apoptosis in human tumor and transformed, but not normal or nontransformed, cells.; Overexpression of IL-2Ralpha has been associated with chemotherapeutic drug resistance, which leads to an overall poor prognosis for the patient. I report that overexpression of IL-2Ralpha in a tumor cell line produces a phenotype with increased transforming activity, proliferation, and drug resistance. Targeting IL-2Ralpha with daclizumab, a monoclonal anti-IL-2Ralpha antibody, leads to decreased proliferation rates, associated with G0-G1 cell cycle arrest, and induction of apoptosis in IL-2Ralpha overexpressing cells.; It has been suggested that proteasome activity is essential for tumor cell proliferation and drug resistance development. I found that peracetate synthetic tea polyphenol analogs are much more potent than natural epigallocatechin-3-gallate [(-)-EGCG] at inhibiting the proteasome in cultured tumor cells, inhibiting proliferation and transforming activity, and induce apoptosis in human cancer cell lines, but not in normal, non-transformed cells. Therefore, these peracetate protected tea polyphenols are more effective than (-)-EGCG and possess great potential to be developed into novel anticancer drugs.; I screened a library of N-thiolated beta-lactams to determine their structure-activity relationship (SAR). The beta-lactams have been shown to induce DNA strand breaks, which ultimately lead to apoptosis. I found that lactam 35 is more potent than lactam 1. Additionally, the stereochemistry of beta-lactams is associated with increased DNA-damaging potency. Testing of enantiomerically pure lactams showed that the beta-configured lactams are the most efficacious. I believe that these three strategies for targeting tumor cell specific apoptosis signaling pathways will help elucidate new therapies for cancer prevention and treatment. |
