化合物信息

Description

Cancer

Description

LBH589 (Panobinostat) is a novel broad-spectrum HDAC inhibitor in MOLT-4 and Reh cells with IC50 of 5 nM and 20 nM, respectively.

Targets

IC₅₀

In Vitro

LBH589 induces apoptosis among MOLT-4 and Reh cells in a time- and dose-dependent manner. Moreover, LBH589 is more potent in MOLT-4 than in Reh cells. LBH589 markedly prevents the growth of both MOLT-4 and Reh cells in a dose-dependent manner at 48 hours. LBH589 treatment causes a 2- to 3-fold increase in the number of cells in the G2/M phase of the cell cycle compared with the control cells. LBH589 is associated with induction of histone H3K9 and histone H4K8 acetylation as well as decreasing levels of c-Myc expression in a dose-dependent manner. LBH589 treatment also increases the levels of p21 expression. LBH589 treatment also decreases the levels of c-Myc after an initial increase at the lowest dose (10 nM) in Reh cells. In addition, LBH589 gives rise to substantial increases in mRNA levels of proapoptosis and DNA repair genes. LBH589 induces increased levels of acetylated histone H3 and H4 at the GADD45G promoter. ^[1] Besides, LBH589 inhibts growth of non small cell lung cancer cell lines (such as human H1299, L55 and A549 with IC50 of 5, 11 and 30 nM, respectively), mesothelioma (such as human OK-6 and Ok-5 with IC50 of 5 and 7 nM, respectively) and small cell lung cancer cell lines (such as human RG-1 and LD-T with IC50 of 4 and 5 nM, respectively). ^[2]

In Vivo

In lung cancer and mesothelioma animal models, LBH589 markedly decreases tumor growth by 62%. LBH589 is equally effective in immunocompetent and severe combined immunodeficien-cymice, suggesting that the inhibition of tumor growth by LBH589 is not due to direct immunologic effects. Daily LBH589, given i.p. at 20 mg/kg for 5 days per week, leading to an average decrease in growth of 70%. Compared with the corresponding control tumors, LBH589 leads to a 53% decrease for H526-derived tumors, a 81% decrease for BK-T-derived tumors, a 76% decrease for RG-1- derived tumors, and a 70% decrease for H69-derived tumors. In contrast to the lack of tumor regression notes in NSCLC and Meso-derived xenografted tumors that are treated under identical conditions and doses, LBH589 results in dramatic tumor regression in SCLC-derived tumors and RG-1-derived tumor. ^[2]

Clinical Trials

Combined with bortezomib,LBH589 is currently in Phase III clinical trial for the treatment of patients with relapsed multiple myeloma.

Features

Description

When either of the two recently approved agents for relapsed/refractory MM (Bortezomib and Lenalidomide) is added to the combination of LBH-589 plus Dexamethasone in MM1S cells, the efficacy is clearly superior to the respective individual agents or double combinations. LBH-589 plus Lenalidomide displays very synergistic results with combination index (CI) less than 0.1. Although the double combinations of LBH-589 plus either Lenalidomide or Bortezomib are highly effective, the antitumor activity increased even further with triple combinations. ^[3] Combination of LBH589 with _Bortezomib enhances cytotoxicity against patient multiple myeloma cells. ^[4] In the Bx-PC3 xenograft model, combination of LBH-589 with Paclitaxel results in a greater anti-tumor effect than LBH-589 alone- with 20% tumor regression and minimal cytotoxicity. ^[5]

Cell Lines

MOLT-4 cell lines and Reh (pre-B cells)

Concentrations

50 nM

Incubation Time

48 hours

Methods

Untreated and LBH589-treated cells [human Ph- acute lymphoblastic leukemia MOLT-4 (T cells) and Reh (pre-B cells)] are stained with annexin V and propidium iodide using annexin V-FITC apoptosis detection kit I. The percentage of apoptotic and nonviable cells is determined by flow cytometry. At least 5 × 10⁴ cells are collected with a CyAn ADP Violet cytometer. Percentage apoptosis is calculated considering all the annexin V-positive plus the annexin V/PI-positive cells; percentage loss of cell viability is calculated considering all the annexin V-positive plus the PI-positive and the annexinV/PI-positive cells.

Animal Models

Severe combined immunodeficiency (SCID) mice with M30 (10×10⁶ cells) or A549 (5×10⁶ cells)

Formulation

Dextrose 5% in water

Doses

10 mg/kg, 20 mg/kg

Administration

Administered via i.p. injection