Strategies for the selective treatment of cancer, including the identification and mechanism of action of compounds that induce G1 cell cycle arrest

Great strides are being made in understanding the signaling pathways involved in initiation and growth of cancers, as well as their abilities to evade treatment. Some of this research is being driven by the development of new chemotherapeutics. Accordingly, there is a broadening spectrum of potential drugs in various stages of clinical trials that can be used to treat this highly invasive disease. The continued development of new chemotherapeutic agents and the identification of novel cellular targets are imperative for the successful treatment of cancer, as well as to gain a more complete understanding of how cells work. Such efforts will bring us closer to the goal of personalizing medicine by targeting specific weaknesses in certain types of cancer. The overarching theme of the work contained herein has been the identification of potential chemotherapeutic agents. Multiple strategies have been employed, from assessment of a compound selective for white blood cell cancers to analysis of potential inhibitors of the poly (ADP-ribose) polymerase (PARP) family of enzymes. The major focus has been the identification of triphenylmethylamides (TPMAs), which induce apoptosis in melanoma cells after causing growth arrest in the G1 phase of the cell cycle. Compounds that induce G1 arrest have potential to avoid many inherent resistances and potentially have a novel macromolecular target since few G1 signaling pathways have been validated as anticancer targets. Investigations into the mechanism of action of these compounds have identified them as disruptors of one or more functions of the endoplasmic reticulum (ER). Disruption of the ER by these compounds has been found to cause cell death by induction of the unfolded protein response.