Colon cancer is a common occurrence in a malignant tumor of the digestive tract with the high mortality rate, but low survival rate. However, colorectal cancer is the fourth most common cancer in the United States, with an estimated 135,430 new cases in 2017. In addition, colon cancer is the second leading cause of cancer deaths in western countries. However, there is a lack of knowledge about the precise underlying mechanism of clinical therapy for colon cancer. Hence, we will introduce an agent-Ipatasertib (GDC-0068)- a novel highly selective ATP-competitive pan-Akt inhibitor, shows a strong antitumor effect in a variety of carcinoma, including colon cancer.
Ipatasertib is an orally active, highly selective and ATP-competitive pan-Akt inhibitor.
Ipatasertib shows IC50 values of 5, 18, 8 nM for Akt1/2/3, respectively. In addition, Ipatasertib exhibits good anticancer activity in both vitro and vivo experiments. According to experimental studies that Ipatasertib led to p53-independent PUMA activation by inhibiting Akt, thereby activating both FoxO3a and NF-κB synchronously that will directly bind to PUMA promoter, up-regulating PUMA transcription and Bax-mediated intrinsic mitochondrial apoptosis.
Ipatasertib (10 µM; 12, 24 h) suppresses colon cancer cell proliferation by p53 irrespectively activating PUMA in vitro. Moreover, Ipatasertib (1, 5, 10, 20 μM; 24 h/10 μM; 3, 6, 12, 24 h) up-regulates the expression level of PUMA in a concentration and time dependent manner in HCT116 cells. Also, Ipatasertib increases the mRNA level of PUMA in HCT116 WT, p53−/−, and DLD1 (p53 mutant) cells. In addition, Ipatasertib (10 µM; 24 h) induces apoptosis through PUMA/Bax pathway in HCT116 cells.
In vivo, Ipatasertib (30 mg/kg; p.o.; single daily for 15 consecutive days) can also exhibit PUMA-dependent antitumor activity in HCT116 WT and PUMA−/− cells xenograft nude mice model.
All in all, Ipatasertib is a promising anticancer agent with efficacy in various cancers including colon cancer.
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