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Return to introduction on drug discovery ~ LeadDiscovery Reports Pancratistatin: A tumor selective apoptosis stimulator Worth an estimated $35 billion in 2003, analysts predict that the sale of oncology therapeutics will grow to $60 billion by 2010. Targeted therapeutics represent one of the most exciting new developments in the field of oncology and include angiogenesis inhibitors; apoptosis stimulators and; signal transduction inhibitors (see Innovative Cancer Therapies: Targeted therapy, a clinical and commercial revolution). Apoptosis stimulators lead by Genta's Genesense are particularly appealing. Canadian researchers are focusing on a stimulator of apoptosis known as pancratistatin. This molecule is particularly exciting because it is a selective inducer of apoptosis effectively killing cancerous cells but leaving healthy cells unharmed. Dr Siyaram Pandey's group at the University of Windsor along with his collaborator Dr. McNulty from McMaster University report that this selectivity is due to the targeting of mitochondria in cancer cells. In parallel with biological studies, chemists are working towards a pharmacophore for pancratistatin which should facilitate both virtual screening for, and the rational design of pancratistatin mimics. Optimization of pancratistatin should hopefully accelerate progress towards the clinic. ****************** Oncology is the third largest pharmaceutical market, behind the cardiovascular and CNS therapy areas, and is currently experiencing strong growth. Worth an estimated $35 billion in 2003, analysts predict that the sector will grow to $60 billion by 2010, yielding a compound annual growth rate of 8% over this period. Major changes are however occurring in the oncology market. Cytotoxics, a cornerstone of oncology, are reaching patent expiry and the last cytotoxic genericization is expected in 2011 (Xeloda). In addition to commercial restraints imposed by genericization, cytotoxic agents are suboptimal because of the frequency and debilitating nature of adverse effects. Thus targeted therapeutics represent one of the most exciting new development in the field of oncology. The pharmaceutical analysts, DataMonitor have recently compared the most promising innovative therapies for the treatment of cancer including angiogenesis inhibitors; apoptosis stimulators and; signal transduction inhibitors (see the DataMonitor report Innovative Cancer Therapies: Targeted therapy, a clinical and commercial revolution). In addition to these therapeutic classes the HDAC inhibitors are fast emerging as a novel approach to cancer (see Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies). Apoptosis, or programmed cell death, consists of a series of characteristic physiological changes that culminate in the phagocytic removal of cells. This process can be activated via either the extrinsic or the intrinsic pathway. The latter is triggered by cellular stress and chemotherapeutic drugs which cause the outer mitochondrial membrane to become permeablized, allowing intermembrane proteins such as cytochrome c and Apaf-1 to be released. The end result is the activation of caspase-9 and down-stream effector caspases including caspase-3 which eventually culminates in cell death. Mitochondrial membrane permibealization is regulated by the BCL2 family of proteins and the mitochondrial permeability transition pore. Genta’s Genasense leads the apoptosis field and analysts predict that its sales will reach $700m by 2012. This forecast is based on Genasense’s likely first-to-market status and a broad range of potential indications headed up by the lead indication, refractory chronic lymphocytic leukaemia. Genasense inhibits the production of Bcl-2 in cancer cells. High levels of Bcl-2 are associated with most types of human cancer and are thought to confer resistance to various treatments. Genta’s approach has therefore been to develop the drug as a combination with standard chemotherapeutic agents with the intention of potentiating the cancer-killing effects of treatment. Genasense is or has been evaluated in combination with Paclitaxel; Irinotecan; Imatiinib; Rituximab; Fludarabine; Cyclophosphamide; Docetaxel; Gemtuzumab. The study by McLachlan et al highlighted here describes another apoptosis stimulator, pancratistatin, a natural compound that was isolated from the spider lily in 1984. Pancratistatin has been shown to induce apoptosis in several cancer cell lines although the biochemical mechanism of this activity is unknown. In their study published in the journal Apoptosis, the Canadian group led by Dr. Siyaram Pandey found that pancratistatin was able to stimulate apoptosis in their model system (human neuroblastoma cell lines). Over 90% of cells had undergone apoptotic death at 24hours. Of considerable importance non-cancerous human hepatic fibroblasts were completely insensitive to the apoptosis stimulating activity of pancratistatin and furthermore, even at extended time-points following a 48hour treatment with pancratistatin, healthy cells were unaffected. This contrast with the classic chemotherapy Taxol which induced apoptosis in both healthy and cancerous cells. Mechanistic studies demonstrated that the level of reactive oxygen species (ROS) as well as caspase-3 and proteosome activity increased in parallel with apoptosis in pancratistatin-treated cancerous cells; these changes were not observed in fibroblasts. Increased mitochondrial release of ROS is indicative of oxidative stress and is able to activate the down-stream apoptosis cascade. The ability of pancratistatin to release ROS suggests a mechanism of action that focuses on cancer cell mitochondria. This was confirmed by further experiments demonstrating that pancratistatin was able to preferentially permeabilize mitochondria in the neuroblastoma cells compared to fibroblasts. By investigating isolated mitochondria the Canadian group demonstrated that pancratistatin acted directly on mitochondria and confirmed that this effect was selective for mitochondria isolated from cancer cells. This important study demonstrates that pancratistatin could form the basis of a new targeted approach to cancer. This apoptosis stimulator appears to be afforded anti-cancer selectivity by virtue of its ability to selectively induce oxidative stress in cancer cells and that this appears to reflect fundamental differences between mitochondria in cancer and healthy cells. Such differences have previously been reported. Abnormal mitochondrial number, size, and shape as well as outer membrane composition is characteristic of many types of cancer cells and furthermore mitochondrial DNA mutations are also common. The exact changes that underlie the selectivity of pancratistatin as well as its molecular target(s) remain to be identified however while such studies are being conducted, data demonstrating the anticancer activity of pancratistatin and its mimics in in vivo models are eagerly awaited. Of interest, Dr Pandey's group has been collaborating with chemists who have refined the pancratistatin pharmacophore ( McNulty et al, 2001) and this is leading to the rational design of synthetic analogs of pancratistatin. The identification of the pharmacophore should also facilitate in silico screening for mimics. Such efforts should hopefully lead to an optimized molecule suitable for entry into the clinic.
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Apoptosis. 2005 May;10(3):619-30. LeadDiscovery and BioPortfolio aims to provide reliable, insightful analysis on the biotechnology industry. However, this information is provided "as is" and no representations or warranties either express or implied of completeness, accuracy, or of any other nature are made with respect to this information. This information is neither an offer to sell nor a solicitation to buy the securities of any company. This information contains forward-looking statements, which involve risks and uncertainties which may not be listed. The biotechnology industry is an emerging industry and the securities of the companies mentioned in this report have a very high degree of risk and volatility. For this reason, this information is supplied on the condition that the reader will make his or her own determination as to its suitability for any purpose prior to any use of this information. The employees and officers of LeadDiscovery and BioPortfolio may hold positions in some or all of the stocks discussed in this report. This abstract has been produced by LeadDiscovery Ltd. Founded by life scientists for life scientists we aim to help industry identify cutting edge drug discovery options and academic/biotech institutions maximize the potential of their research. Abstracts strictly reflect the opinion of LeadDiscovery's editorial panel. While all reasonable efforts are made to ensure the accuracy of information provided LeadDiscovery and the publisher BioPortfolio, takes no responsibility for incorrect or misleading information. LeadDiscovery is designed for educational and drug development purposes only and is not intended or designed to offer medical advice or advice of any sort, and must not be used for such purpose. The information provided through LeadDiscovery and BioPortfolio should not be used for diagnosing or treating a health problem or a disease and no reliance should be placed on any information contained in this abstract or elsewhere on LeadDiscovery's and BioPortfolio's website. It is not intended to be a substitute for professional care. If you have or suspect you may have a health problem, you should consult your physician or other health care provider. |
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