Pancratistatin - Biological Activity

Biological Activity

The medicinal and toxic properties of Amaryllidaceae family were first discovered by the Greeks. They used the oil from Narcissus species for the treatment of cancer. Consequently, efforts have been made to isolate the active ingredients responsible for this antitumor activity. Some 48 alkaloids bearing a variety of carbon skeletons have been isolated from Narcissus species. One group of these alkaloids does not contain basic nitrogen atoms and is represented by an isoquinolinone structure. The most widely known compounds of this group are narciclasine, lycoricidine and Pancratistatin (PST). The most frequently used term in the literature to describe this group of alkaloids is the isocarbostyrils. All these natural products have demonstrated potent in vitro cytotoxicity against cancer cell lines and potent in vivo antitumor activity. Therefore, this family as a whole is of interest as a potential source of new lead structures for the development of a future generation of anticancer drugs.

PST displays selective potent toxicity against human tumour cells by showing a strong tendency to attack the Mitochondria of the cancer cells while having no influence on normal cells. Studies have shown that Pancratistatin rapidly and efficiently induces apoptosis (programmed cell death) in various types of cancer cell lines, including breast, colon, prostate, neuroblastoma, melanoma and leukemia. Most importantly, when Pancratistatin was tested for toxicity on peripheral white blood cells from healthy volunteers, there was little or no demonstrable effect on their viability and nuclear morphology, indicating the relative specificity of this compound for cancer cells.

Some of the recent insights regarding the mode of action of PST include inhibition of the cell cycle from G0/G1 to S phase and powerful antiparasite activity. As mentioned previously, Pancratistatin, unlike other anticancer drugs, discerns between normal and cancerous cells. Pancratistatin does not cause DNA double-strand breaks or DNA damage prior to the execution phase of apoptosis in cancer cells. Parallel experimentation with VP-16, a currently used medication for cancer treatment, indicated that VP-16 causes substantial DNA damage in normal non-cancerous blood cells, while Pancratistatin does not cause any DNA double-strand breaks or DNA damage in non-cancerous cells. Pancratistatin induces apoptosis in cancer cells using non-genomic targets, and more importantly does not seem to have any effect on non-cancerous cells, presenting a significant platform to develop non-toxic anticancer therapies.

The capability of Pancratistatin to selectively induce apoptosis in cancer cells is an exciting finding and makes it a suitable anti-cancer agent. Since Pancratistatin shows little structural similarity to any DNA intercalating drug or to paclitaxel derivatives, it appears to be non-genotoxic. Also, Pancratistatin may act upon target while allowing selective induction of apoptosis in cancer cells. Recent studies have also shown that the bulbs of Pancratium contain a new phenanthridone biosynthetic product designated Pancratistatin that proved to be effective (38-106% life extension at 0.75-12.5 mg/kg dose levels) against the murine P-388 lymphocytic leukemia. Pancratistatin also markedly inhibited (ED50, 0.01 microgram/ml) growth of the P-388 in vitro cell line and in vivo murine M-5076 ovary sarcoma (53-84% life extension at 0.38-3.0 mg/kg).