Napabucasin

Target: Signal transducer and activator of transcription 3 (Stat3)

IC50: 0.395 μM (Bulk cells), 0.142 μM (Cancer stem cells)

Napabucasin, also named (BBI608), is an orally available small molecule by the ability to inhibit gene transcription of STAT3 and cancer stemness properties and suppresses spherogenesis or kills stemnesshigh cancer cells isolated from several kinds of cancer types [1]. Stat3 is critically important for maintaining cancer stemness.

In vitro: Napabucasin (1 μmol/L) not only decreased cell viability, migration, colony formation, and survival with cell cycle arrest, and increased cell apoptosis and sensitivity to docetaxel, but also obviously blocked PrCSCs sphere formation and killed them in vitro [1]. Napabucasin (1, and 2 μmol/L) decreased the expressions of stemness markers such as Nanog, Klf4, survivin, C-myc, and β-catenin [1].

In vivo: Napabucasin (40 mg/kg, i.p. injection) inhibited tumor growth on prostate cancer (PCa) mouse xenograft models, the PC-3 cells or 22RV1 cells were inoculated into nude mice. In addition, Napabucasin suppressed the self-renewal of stemness-high prostate cancer (PCa) cells in vivo [1]. Moreover, Napabucasin (20 mg/kg, i.p. injection) effectively blocked cancer relapse and metastasis in xenografted human cancers including PaCa-2 human pancreatic cancer and HT29 human colon cancer [2].

References:
1.  Zhang Y, Jin Z, Zhou H, Ou X, Xu Y, Li H, et al. Suppression of prostate cancer progression by cancer cell stemness inhibitor napabucasin. Cancer Med. 2016;5(6):1251-8.
2.  Li Y, Rogoff HA, Keates S, Gao Y, Murikipudi S, Mikule K, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015;112(6):1839-44.

Suppression of prostate cancer progression by cancer cell stemness inhibitor napabucasin.[Pubmed:26899963]

Cancer Med. 2016 Jun;5(6):1251-8.

A small population of cells with stem cell-like properties in prostate cancer (PCa), called prostate cancer stem cells (PrCSCs) or prostate stemness-high cancer cells, displays highly tumorigenic and metastatic features and may be responsible for the therapy resistance. A small molecule, Napabucasin (BBI608), recently have been identified with suppression of stemness-high cancer cells in a variety of cancers. However, the effects of Napabucasin on PCa cells as well as PrCSCs isolated from PCa cells have not yet been defined. The effect of Napabucasin on PCa cells in cell proliferation, colony formation, and cell migration in vitro were measured by MTS, colony formation assay, and Transwell, respectively. Flow cytometry was employed to evaluate cell cycle and cell apoptosis, and the effect on tumorigenesis in vivo was examined by tumor growth assays. Furthermore, the role of Napabucasin on self-renewal and survival of PrCSCs was evaluated by their ability to grow spheres and cell viability assay, respectively. Western Blot and qRT-PCR were used to determine the effect of Napabucasin on the expressions of stemness markers. Decrease in cell viability, colony formation, migration, and survival with cell cycle arrest, higher sensitivity to docetaxel in vitro, and repressed tumorigenesis in vivo was observed upon Napabucasin treatment. More importantly, Napabucasin can obviously inhibit spherogenesis and even kill PrCSCs in vitro. Downregulation of stemness markers was observed after PrCSCs were treated with Napabucasin. This study demonstrates that Napabucasin may be a novel approach in the treatment of advanced PCa, specifically for castration-resistant prostate cancer (CRPC).

Suppression of cancer relapse and metastasis by inhibiting cancer stemness.[Pubmed:25605917]

Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44.

Partial or even complete cancer regression can be achieved in some patients with current cancer treatments. However, such initial responses are almost always followed by relapse, with the recurrent cancer being resistant to further treatments. The discovery of therapeutic approaches that counteract relapse is, therefore, essential for advancing cancer medicine. Cancer cells are extremely heterogeneous, even in each individual patient, in terms of their malignant potential, drug sensitivity, and their potential to metastasize and cause relapse. Indeed, hypermalignant cancer cells, termed cancer stem cells or stemness-high cancer cells, that are highly tumorigenic and metastatic have been isolated from cancer patients with a variety of tumor types. Moreover, such stemness-high cancer cells are resistant to conventional chemotherapy and radiation. Here we show that BBI608, a small molecule identified by its ability to inhibit gene transcription driven by Stat3 and cancer stemness properties, can inhibit stemness gene expression and block spherogenesis of or kill stemness-high cancer cells isolated from a variety of cancer types. Moreover, cancer relapse and metastasis were effectively blocked by BBI608 in mice. These data demonstrate targeting cancer stemness as a novel approach to develop the next generation of cancer therapeutics to suppress cancer relapse and metastasis.