Blockade of the interaction between Bcr Abl and PTB1B by small molecule SBF 1 to overcome imatinib resistance of chronic myeloid leukemia cells.
In this study, a synthetic steroidal glycoside SBF 1 had strong and preferential antitumor effects on the human chronic myeloid leukemia (CML) cell line K562 and its imatinib resistant form K562/G. SBF 1 induced apoptosis in both cell lines without any effect on cell cycle arrest. It also inhibited the activation of PI3K/Akt pathway members, such as PI3K and Akt, as well as downstream targets mTOR and Bcl 2. Moreover, the degradation of the Bcr Abl protein was induced by SBF 1 in a concentration and time dependent manner. Using a pull down assay, SBF 1 was found to bind to both Bcr Abl and PTP1B and disrupted the interaction between them. SBF 1 triggered the degradation of Bcr Abl through ubiquitination via the lysosome pathway. Taking together these findings, this study, for the first time, suggests that the blockade of the interaction between Bcr Abl and PTP1B may be a feasible strategy for the treatment of CML, especially CML with resistance to Bcr Abl kinase inhibitor imatinib. Our study also indicates that SBF 1 may serve as a leading compound for novel anti CML therapeutic agents.
Cancer letters