Identification of stemonamide synthetic intermediates as a novel potent anticancer drug with an apoptosis‐inducing ability

Abstract

We previously demonstrated that Pim-3, a protooncogene with serine/threonine kinase activity, was aberrantly expressed in malignant lesions but not in normal tissues of endoderm-derived organs, including pancreas, liver, colon and stomach. Moreover, aberrantly expressed Pim-3 can prevent tumor cell apoptosis by inactivating a proapoptotic molecule, Bad, and enhancing the expression of an antiapoptotic molecule, Bcl-X L . These observations prompted us to speculate that a chemical targeting Pim-3 kinase may be a good candidate for a novel type of anticancer drug. Hence, we screened various low-molecule compounds by examining their capacity to inhibit Pim-3 kinase activity in vitro. We observed that some synthetic intermediates of stemonamide can inhibit in vitro activities of Pim-3 kinase and its related kinases, such as Pim-1 and Pim-2. Moreover, these compounds inhibit in vitro cell proliferation of various human pancreatic, hepatocellular and colon cancer cell lines. Furthermore, the compounds can induce apoptosis of human pancreatic cancer cell lines in vitro by reducing the amount of phospho-Ser 112 -Bad, but not total amounts of Bad and Pim-3. Finally, when the compound was administered to nude mice injected with a human pancreatic cancer cell line, it retarded tumor growth by increasing apoptotic cell numbers and decreasing proliferating cell numbers without causing serious adverse effects on blood counts. These observations indicate that the chemicals and its related compounds may be effective for the treatment of tumors of endoderm-derived organs, particularly the pancreas.Pancreatic cancer is one of the most common causes of death from cancer. Most patients are diagnosed at an advanced stage; fewer than 20% of the patients present with potentially resectable cancer, whereas the remaining patients have locally advanced, unresectable or metastatic disease.

A Novel Regulatory Mechanism of Pim-3 Kinase Stability and Its Involvement in Pancreatic Cancer Progression

“…Among them, 1,6-dihydropyrazolo [4,3-c]carbazoles, 3,6-dihydropyrazolo [3,4-c]carbazoles, and pyrrolo[2,3-g]indazoles could be used as an interesting molecular tool to study Pim-3 biological functions (52). Consistently, we also demonstrated that stemonamide synthetic intermediates derivative can inhibit Pim-3 as well as Pim-1 and Pim-2 activities and can reduce tumor growth in vivo xenograft models using a human pancreatic cancer cell line without causing major adverse effects (55,56). TCTP but not Pim-3 expression …”

Aberrant Expression of Pim-3 Promotes Proliferation and Migration of Ovarian Cancer Cells

“…By now, several independent groups have developed small-molecule inhibitors against Pim kinases (Akue-Gedu et al, 2012;Gavara et al, 2013). Stemonamide synthetic intermediates derivative can inhibit Pim-3 as well as Pim-1 and Pim-2 activities and can reduce tumor growth in vivo xenograft models using a human pancreatic cancer cell line without causing major adverse effects (Li et al, 2010;Wang et al, 2013). Since our results showed Pim-3 might be involved in ovarian cancer proliferation and metastasis, Pim-3 might also be an ideal target for ovarian cancer therapy.…”

Pim-2 phosphorylation of p21Cip1/WAF1 enhances its stability and inhibits cell proliferation in HCT116 cells

“…Interestingly, SGI-1776 inhibits not only Pim-2 kinase activity, but also p21 phosphorylation (Mumenthaler et al, 2009), which could result in a reduced levels of p21 protein in tumor cells. The application of newly identified Pim-2 inhibitors may contribute greatly to cancer therapy in the near future (Amaravadi and Thompson, 2005;Tao et al, 2009;Li et al, 2009;Akue-Gedu et al, 2009;Qian et al, 2009;Lin et al, 2010). …”