Boosani “Endogenous angiogenesis inhibitors affecting cell survival pathways”

by Selleckchem | Sep 13 2011

Phosphatidylinositol 3-kinases (PI3 kinases) are a group of enzymes categorized into three different classes, among them class I isoforms are well characterized (Stein, 2001). These kinases are the key enzymes that are vital for cell survival with essential role in several cellular functions such as growth, proliferation, differentiation, motility, and intracellular signaling. PI3 Kinases are activated by tyrosine kinases with Akt being the downstream effector molecule (Hennessy et al., 2005).
PI3 Kinase was reported to be overactive in diverse cancer types with genetic aberrations in the PI3 Kinase pathway (Kang et al., 2005). With PI3 Kinase proven to be more specific for cancer, several inhibitors have been identified and many of which are in clinical trials for use in cancer therapy. However, as with many of the chemically synthesized drugs, the potential defense mechanism of acquired drug resistance in the host cells would eliminate the use of such synthetic inhibitors for the cancer treatment. It is at this point, an endogenous inhibitor would become a promising candidate for cancer treatment which could overcome the problem of acquired drug resistance (Kerbel et al., 2001).
A major pathological phenomenon that is associated with several cancer types especially the ones with solid tumors is Angiogenesis. Angiogenesis is a physiological and pathological phenomenon during which new blood vessels originate from the pre-existing mature vessels where growth factors, especially VEGF and bFGF, greatly contribute to this de novo synthesis. More than 70 major pathological conditions are associated with Angiogenesis which include many cancers, cardiovascular disease, blindness, arthritis, complications of AIDS, diabetes, Alzheimer's disease, psoriasis, endometriosis, adiposity etc. where profuse formation of the new blood vessels is observed and this uncontrolled growth of new blood vessels essentially contributes to the disease phase (Folkman, 1995). However during normal physiological growth and development of the body, our body's innate mechanism maintains an angiogenic balance by employing endogenous angiogenesis inhibitors preventing further growth of new blood vessels. Some of the endogenous angiogenesis inhibitors identified were listed in the below table.
Under pathological conditions, for tumors to grow beyond their benign size, tumor secreted factors initiate tumor angiogenesis in need of nutrients and blood supply. Several tumor associated factors have been identified that are either directly or indirectly associated with angiogenesis. Also, several endogenous angiogenesis inhibitors have been discovered in the last few decades and their list is ever increasing. Due to page limitations, the below table only shows fifty such endogenous angiogenesis inhibitors. These endogenous antiangiogenic molecules can be further categorized into two groups, matrix derived and non-matrix derived.
What makes these endogenous angiogenesis inhibitors to be more promising is their ability to inhibit cell survival pathways, however many of these endogenous molecules have not been reported as how they could affect or regulate PI3 Kinase activity. Owing to their endogenous origin, the available literature suggests that the biological activities of these inhibitors could be mediated through multiple pathways. Although many of these molecules are not fully characterized, the known mechanisms by which these endogenous anti-angiogenic molecules regulate angiogenesis include both outside-in and inside-out signaling.
Research so far on these endogenous molecules elucidates specific mechanisms that either directly affect PI3 Kinase activity such as Tumstatin (Maeshima et al., 2002), or indirectly by a mechanism that affects either upstream or downstream molecules such as FAK, Akt, Ras etc., eventually affecting the cell survival pathway, and inhibiting tumor growth. Some of these endogenous antiangiogenic molecules such as Angiostatin, Endostatin, PF4, Antithrombin III, Interferons etc., are presently under clinical trials involving several cancer types. With an added advantage of being endogenous origin, identification of the abilities of these endogenous angiogenesis inhibitors to inhibit tumor growth by studying their precise molecular mechanisms and inhibition of tumor specific pathways such as PI3 Kinase pathway, would prove them to be very effective candidates for cancer treatment, and the results from such clinical trials involving these endogenous molecules would be much awaited with high anticipations.