There is substantial scientific evidence that human prolactin is associated with the growth of certain cancers as well as resistance to platinum and taxane therapies (Asai-Sato, Nagashima et al. 2005; Howell, Anderson et al. 2008; LaPensee, Schwemberger et al. 2009; Levina, Nolen et al. 2009). Our preclinical data indicate that the inhibition of the in vivo effects of prolactin on cancer cells (through antagonism with Prolanta™) may have a therapeutic effect on gynecological and other cancers.
Human Prolactin Production and Function. Human prolactin is a single-chain polypeptide of 200 amino acids with a molecular weight of approximately 23,000 Daltons. Prolactin is both a circulating hormone and a cytokine. It is primarily associated with the development and function of the reproductive system, but also may be involved in angiogenesis and regulation of the immune system (Goffin, Binart et al. 2002). Prolactin is mainly synthesized and secreted by lactotroph cells in the anterior pituitary gland, but is also produced at sites outside the pituitary gland, such as mammary gland, ovary, uterus, prostate, lymphocytes, brain, and several types of tumor cells (Sabharwal, Glaser et al. 1992; Freeman, Kanyicska et al. 2000; Levina, Nolen et al. 2009). This extra-pituitary prolactin can act as a tumor growth factor in an autocrine-paracrine fashion, both on the tumor cells that secrete prolactin (autocrine) as well as on nearby cells (paracrine) (Ben-Jonathan, Liby et al. 2002).
Prolactin binds with its cell surface receptor through dimerization, activating various signaling pathways. Prolactin signals through a complicated web of kinases, including Janus kinase 2 (JAK2), Src kinase, phosphatidylinositol 3′-kinase (PI3K), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK). The best-characterized signaling pathway is the JAK2/STAT5 pathway, which has been shown to be critical for prolactin actions in mammary gland development. This pathway plays a central role in cell proliferation, differentiation and cell death. In addition, the ras/raf/MAPK pathway is also activated by prolactin and may be involved in the proliferative effects of the hormone (Freeman, Kanyicska et al. 2000; Gutzman, Miller et al. 2004).
Prolactin increases DNA synthesis (Peyrat, Djiane et al. 1984) and the expression of bcl-2 in breast cancer cells in vitro, and decreases the release of mitochondrial cytochrome C (Peirce and Chen 2004). Prolactin also activates the enzyme, glutathione-S-transferase, that detoxifies platinum drugs, doxorubicin, cyclophosphamide and etoposide, contributing to the resistance of cancer cells to chemotherapies (LaPensee, Schwemberger et al. 2009). Accordingly, the antagonism of prolactin by Prolanta may increase the effectiveness of these chemotherapies (Asai-Sato, Nagashima et al. 2005; Howell, Anderson et al. 2008; LaPensee, Schwemberger et al. 2009), and our own data indicates synergy with taxanes.
Dopamine agonists such as bromocriptine suppress pituitary prolactin production (Utian, Begg et al. 1975). Bromocriptine has been evaluated as an anti-cancer agents in a clinical trial but was not effective, potentially because this agonist has no effect on non-pituitary prolactin production (there are no dopamine receptors on cancer cells) (Bonneterre, Mauriac et al. 1988). Oncolix believes the prolactin receptor must be blocked through an antagonist like Prolanta™ in order to antagonize the activity of extra-pituitary prolactin.
Prior Evidence of Prolactin in Ovarian Cancers. Levina et al have shown that serum levels of prolactin are significantly elevated in women with a strong family history of ovarian cancer. Increased expression of the prolactin receptor has been observed in ovarian and endometrial tumors, signifying the importance of prolactin signaling in malignant conditions (Mor, Visintin et al. 2005; Levina, Nolen et al. 2009). Additionally, prolactin mRNA was detected in ovarian and endometrial tumors, indicating the presence of an autocrine loop. Prolactin potently induced proliferation in several ovarian and endometrial cancer cell lines (Asai-Sato, Nagashima et al. 2005). Prolactin also activated the ras oncogenic signaling in normal ovarian epithelial cells such that the malignantly transformed cells were able to form tumors in immunodeficient mice (Levina, Nolen et al. 2009).
Prior Evidence of Prolactin in Breast Cancers. Evidence supports the hypothesis that prolactin is also intimately involved in the pathogenesis of breast cancer (Clevenger, Chang et al. 1995; Vonderhaar 1998; Vonderhaar 1999; Llovera, Pichard et al. 2000; Llovera, Touraine et al. 2000). Prior studies have demonstrated that the inhibition of the binding of prolactin to the prolactin receptor inhibits breast cancer cell growth (Fuh and Wells 1995; Chen, Ramamoorthy et al. 1999; Chen, Holle et al. 2002).
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