Molecule

Description

Cancer

Description

LY294002 is a PI3K inhibitor for p110α, p110δ and p110β with IC50 of 0.5 μM, 0.57 μM and 0.97 μM, respectively.

Targets

IC₅₀

In Vitro

LY294002 inactivates Akt/PKB, consequently inhibiting cell proliferation and inducing apoptosis. LY294002 demonstrates a remarkable growth-inhibitory and apoptosis-inducing effect in these colon cancer cell lines, with decreased expression of phosphorylated Akt (Ser473). ^[2]LY294002 induces marked nuclear pyknosis and diminished cytoplasmic volume in the tumor cells. Thus, LY294002 markedly inhibits ovarian cancer cell proliferation in vitro. LY294002 induces specific G1 arrest in cell growth, leading to almost complete inhibition of melanoma cell proliferation and partial inhibition of MG-63 (osteosarcoma cell line) proliferation. The effect of LY294002 on cell cycle progression may provide insights into a possible link between the PI3K activation pathway and cancer cell cycle regulation. ^[3]

In Vivo

LY294002 also resultes in suppression of tumor growth and induction of apoptosis, especially in the LoVo tumors, and therefore shows remarkable effectiveness in the mouse peritonitis carcinomatosa model. ^[2] LY294002 significantly inhibits growth and ascites formation of ovarian carcinoma. ^[3]

Clinical Trials

LY294002 is currently in Phase I clinical trials in patients with cancers.

Features

kinase assays

PI3K inhibition by LY294002 is determined in a radiometric assay using purified, recombinant enzymes with 1?μM ATP. The kinase reaction is carried out for 1?hour at room temperature (24^oC) and is terminated by addition of PBS. IC50 values are subsequently determined using a sigmoidal dose–response curve fit (variable slope). CK2 and GSK3β (glycogen synthase kinase 3β) inhibition is established by kinase selectivity screening. LY294002 is tested against the Upstate panel of kinases in 10?μM ATP.

Cell Lines

Colon cancer cell lines DLD-1, LoVo, HCT15, and Colo205

Concentrations

0–50 μM

Incubation Time

0–48 hours

Methods

1.0×10⁵ cells (100 μL volume/well) are inoculated into 96-well microtiter plates. LY294002 is added to triplicate wells and cultured at 37^oC for 0–48 hours. After treatment, 10 μL of Premix WST-1 are added to each microculture well, and the plates are incubated for 60 minutes at 37^oC, after which absorbance at 450 nm is measured with a microplate reader.

Animal Models

Two groups of athymic nude mice (5–7 weeks) are inoculated i.p. with OVCAR-3 cells

Formulation

Dissolved in DMSO plus 0.25 ml of PBS

Doses

0–100 mg/kg

Administration

Administered via i.p.