in-1130 and Prostatic-Neoplasms

Transforming growth factor-beta is a potent immune suppressor that is over expressed by most malignant cells to evade the host immune response. Thus, a potential anticancer therapeutic strategy is the inhibition of transforming growth factor-beta signaling.. We investigated the specificity and the antitumor effect of IN-1130, a novel small molecule inhibitor of the transforming growth factor-beta type I receptor ALK-5.. IN-1130 inhibited transforming growth factor-beta induced cell death and gene transcriptional activity in a concentration dependent manner in the human hepatoma cell line HepG2. Simultaneously immunoblot analysis demonstrated that IN-1130 inhibited the Smad2 phosphorylation induced by transforming growth factor-beta. To determine the specificity of IN-1130 for transforming growth factor-beta signaling the effect on active and bone morphogenic protein signaling was subsequently investigated. Results demonstrated that IN-1130 did not inhibit bone morphogenic protein signaling. However, active signaling was blocked by IN-1130 in a concentration dependent manner. Furthermore, immunoblot analysis for phospho-Smad2 following transfection with constitutively active ALK-1 to 7 demonstrated that IN-1130 inhibited ALK-4 (active receptor type IB), 5 (TbetaRI) and 7 (nodal type I receptor). To investigate the antitumor effect of IN-1130 WT mice were injected subcutaneously with the murine prostate cancer cell line Tramp C2. Seven days later IN-1130 was administered intraperitoneally daily for 30 days. Results demonstrated a dramatic decrease in tumor volume in association with an enhanced immune response in the treatment group.. Taken together these results demonstrate that IN-1130 is a relatively nontoxic inhibitor of ALK-4/5/7 that may potentially treat prostate cancer.

Topics: Animals; Drug Screening Assays, Antitumor; Humans; Imidazoles; Male; Mice; Prostatic Neoplasms; Quinoxalines; Tumor Cells, Cultured