MODE OF ACTION
The cells in our bodies are continuously involved in a carefully orchestrated system of programmed growth, division, rest, and death. The regulation of these cellular pathways is essential in order to maintain tissue viability and bodily health. The transition of a healthy cell to a precancerous or cancerous cell is initiated by the disruption of these regulatory pathways. Cancer cells then redirect the cellular systems to allow for uncontrolled cell growth, replication, and resistance to programmed cell death (apoptosis).
Caspases are essential for apoptosis and are deemed the “executioner” proteins for their roles in the cell. Apoptosis is regulated by the inhibitor of apoptosis protein (IAP) family of proteins, through their inhibition of caspase-induced cell death. One of the IAP family members, survivin, is over-expressed in pre-cancerous and cancerous cells, and rarely found in healthy adult cells. Due to their high survivin expression, tumor cells are prevented from entering the caspase-induced cell death pathway that would lead to their destruction. Survivin is therefore a powerful anticancer target. Survivin is considered a primary target for Terameprocol’s effects on cancer cells.
Another mechanism by which tumor cells grow uncontrollably is by deregulating their cell cycle process. Cdc2 (cyclin-dependent kinase-1) is one of several kinase proteins controlling cell division and is frequently de-regulated in cancer cells. Cdc2 is also involved in the activation of survivin. In addition, growing tumors require a constant supply of essential nutrients and oxygen. Cancer cells achieve their nutrient needs by secreting Vascular Endothelial Growth Factor (VEGF) to induce new blood vessel formation within the tumor mass.
Key proteins as mentioned above are involved in the regulation of the signaling pathways that control cell growth, division and death. Some of these proteins are significantly altered in cancer cells. Transforming the gene sequence on DNA to an RNA message (a process called transcription) that can then be converted to protein is essential to the regulation of protein production.
Terameprocol is a transcription inhibitor. It selectively reduces transcription of genes that have promoters controlled by the Sp1 factor, such as survivin, cdc2 and VEGF. By blocking production of survivin, cdc2 and VEGF, terameprocol can attack the tumors by inducing tumor cell death, preventing further growth, and starving the tumors by restricting growth of their blood supply.
Given the targets of terameprocol, the drug is expected to show specific tumoricidal activity with limited systemic toxicity. The specificity of terameprocol in cancer cells is derived from being able to access those genes that are highly active in cancer (through their “open” DNA conformation) to repress their expression through Sp1 binding inhibition, while normal cells do not have the same gene expression profile or DNA conformation accessible to terameprocol binding. Survivin especially is almost exclusively present in tumor cells and terameprocol can inhibit its production by accessing the promoter region of the survivin gene to prevent Sp1 binding.
Terameprocol has been shown to arrest growth of a variety of human cells in vitro, the majority of which are part of the NCI panel of 60 cancer cell lines, including solid tumor cell lines (bladder, breast, colorectal, liver, lung, ovarian, pancreatic, prostate and cervical carcinomas), and erythroleukemia cells. In vivo, terameprocol also decreases tumor cell growth and exhibits antitumor activity in a large number of tumor xenograft models, including human bladder, breast, colorectal, liver, ovarian, pancreatic, prostate and cervical carcinomas, and erythroleukemia, without apparent toxicity.
Terameprocol and other NDGA derivatives also prevent proliferation of human immunodeficiency virus (HIV), herpes simplex virus (HSV), and human papillomavirus (HPV). This is achieved through the deactivation of viral Sp1-dependent promoters that are essential for viral propagation. This suggests that terameprocol may also be an important therapy for serious viral infections.
Research in collaboration with North Carolina State University has shown potential benefits of terameprocol in treating pneumonia and other symptoms related to influenza virus infection.