AKT inhibition by triciribine alone or as combination therapy for growth control of gastroenteropancreatic neuroendocrine tumors

Abstract

Abstract. Up-regulation of phosphatidylinositol-3-kinase (PI3K)-AKT signaling facilitates tumor cell growth and inhibits cell demise. The AKT-pathway also plays an important role in cytostatic therapy resistance and response to hypoxia and angiogenesis. Using real-time cell proliferation assay we examined the potency of triciribine in three distinct neuroendocrine gastrointestinal tumor cell lines. Also we investigated triciribine's induction of apoptosis and effects on a broad range of cancer-associated gene products. Furthermore, we characterized the role of PTEN as a possible predictor of sensitivity to triciribine in GEP-NETs. We also looked for additive anti-neoplastic effects of triciribine when combined with conventional cytostatic drugs or other targeted drugs, affecting different molecules of the PI3K-AKT-pathway and we assessed the potency of triciribine to inhibit tumor growth in vivo, by using the chick chorioallantoic membrane assay. Treatment of insulinoma (CM) or gut neuroendocrine tumor cells (STC-1) with triciribine significantly reduced tumor cell growth by 59% and 65%, respectively. By contrast, the highly expressing PTEN carcinoid cell line BON did not respond, even at higher doses. Combinations of triciribine with classic cytostatic drugs as well as drugs targeting other molecules of the PI3K-AKT-pathway led to synergistic anti-proliferative effects. Additional in vivoevaluations confirmed the anti-neoplastic potency of triciribine. Thus, our data show that inhibition the AKT-pathway potently reduces the growth of GEP-NET cells alone or in combination therapies. AKT inhibition may provide a rationale for future evaluations. IntroductionGastroenteropancreatic neuroendocrine tumors (GEP-NETs), often synonymously called carcinoids, are a very heterogeneous group of neoplasms. Originally thought of as representing a rather homogeneous group, advances in the knowledge of molecular changes within different tumor entities of the GEP-NETs led to the classification system of the WHO in 2000 (1), later supplemented with additional studies (2).With a reported incidence of 2-3:100,000 GEP-NETs are relatively rare, but the 5-year survival rate is only about 67% (3,4). For localized tumors, systemic symptoms can be absent, since often its products, excess biogenic amines and hormones, are mostly cleared by the liver. Metastasized tumors, however, have often incapacitating symptoms, e.g., for the carcinoid syndrome including diarrhea, flushing, wheezing and skin rashes.The treatment of choice in locally defined tumors is still surgical resection (5). However, at presentation, about 80% of patients have already developed liver or lymph node metastases. In the advanced stages, the medical treatment options are still poor. Currently, different chemotherapeutic regimens are used, depending amongst others on the differentiation of the tumor, including etoposide plus cisplatin or streptozotocin with 5-FU or doxorubicin (6-8). However, response rates of 0-30% are still disappointing. In well-differentiated tumors...

PI3K-AKT-mTOR-Signaling and beyond: the Complex Network in Gastroenteropancreatic Neuroendocrine Neoplasms

“…In vitro data concerning the response of neuroendocrine pancreatic (BON) and insulinoma (CM) cell lines towards triciribine inhibition suggest that PTEN might also influence the sensitivity of pNENs cells to Akt inhibition 169-171.…”

Differential Protein Expression in Small Intestinal Neuroendocrine Tumors and Liver Metastases

“…[11–14] Other groups have similarly shown the importance of the phosphatidylinositol-3-kinase (PI3K)-AKT pathway in tumor cell growth and angiogenesis in pancreatic NET cell lines, as well as in human clinical trials. [15–17]…”

Anti-tumour activity of two novel compounds in cisplatin-resistant testicular germ cell cancer

“…In the present study, we investigated the suitability of HP-2 and HP-14 for growth inhibition of platinum-resistant TGCT cells, and examined the anti-neoplastic and anti-angiogenic effects in vivo by using a modified chicken chorioallantoic membrane (CAM) model (Gloesenkamp et al , 2012b). Moreover, we investigated possible additive anti-neoplastic and/or cisplatin-resensitising effects of a combination treatment of the HP compounds together with cisplatin.…”