Cell lines

HCT116 Bax-/- and HCT116 p53-/- cells

Preparation method

The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

1.25, 2.5, 5 and 10 μM; 24, 48 or 72 hours

Applications

In TRAIL-sensitive HCT116 p53-/- cells, TIC10 induced an increase in sub-G1 DNA content suggestive of cell death in a p53-independent and Bax-dependent manner. In TRAIL-resistant Bax-null HCT116 human colon cancer cells, TIC10 (10 μM, 72 h) dose-dependently increased TRAIL mRNA and induced TRAIL protein localization on the cell surface in a p53-independent manner.

Animal models

Female athymic nu/nu mice subcutaneous xenografted with HCT116 p53-/- tumor and MDA-MB-231 human triple-negative breast cancer.

Dosage form

50, 80 or 100 mg/kg; intraperitoneal injection; administered on days 0, 3, and 6

Application

In mice bearing the HCT116 p53-/- xenograft, TIC10 caused tumor regression. TIC10 also induced regression of MDA-MB-231 human triple-negative breast cancer xenografts.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

TIC10 (TRAIL-inducing compound 10) is a potent and stable small molecule that is orally active. It induces TRAIL transcriptionally independent of p53 and crosses the blood-brain barrier. [1]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an apoptosis inducer in a variety of human cancer cell lines. It also acts as a tumor suppressor during immune surveillance but the function is lost in cancer progression. [1]

TIC10 caused a prominent and long-lasting production of TRAIL on cell surface of tumor cell.

TIC10 also led to TRAIL-mediated apoptosis in HCT116 p53-/- cells. In addition, TIC10 inactivated Akt and ERK cooperatively lead to the nuclear translocation of Foxo3a and ensuing TRAIL up-regulation. [1]

In mouse caner xenograft, TIC10 showed TRAIL-dependent antitumor effect. It caused tumor-specific cell death by RAIL-mediated direct and bystander effects. TIC10 is also an effective antitumor agent for orthotopic human glioblastoma multiforme tumors. [1]

Reference:
1. Allen JE, Krigsfeld G, Mayes PA et al. Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci Transl Med. 2013 Feb 6;5(171):171ra17.