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  • Moreover we examined inhibition of GLI mediated mRNA express

    2022-08-09

    Moreover, we examined inhibition of GLI-mediated mRNA expression by 1. Colubrinic Gemcitabine australia (1) inhibited the mRNA production of PTCH in PANC1 cells in the dose-dependent manner. This result clearly shows 1 inhibits GLI-mediated transcription (Fig. 6).
    Discussion In this study, we identified three pentacyclic triterpenes as potent inhibitors of the Hh/GLI signaling pathway. Betulinic acid (2) has been studied as a cytotoxic compound against several caner cell lines, while colubrinic acid (1), and alphitolic acid (3) have been little reported. In this study, 1, 2 and 3 showed inhibitory activity in the Hh/GLI signaling pathway. Compound 2 was reported to induce apoptosis by activation of mitochondria,25, 26, 27 to perturb cell cycle progression; however, the precise mechanism is still under investigation. The overexpression of apoptosis-inhibition protein BCL2 may rescue cancer cells from cytotoxic effects of 2, and 2 induced apoptosis in cancer cells by decreasing the mRNA expression of Bcl2 and Cyclin D1. It has also been reported that the Hh/GLI signaling pathway in cancer cells regulates the expression of Bcl2 and Cyclin D1. Because we demonstrated that 2 acts as a potent inhibitor of the Hh/GLI signaling pathway in this study, this signal inhibition would be one reason for the decrease of Bcl2 and Cyclin D1 expression, which causes the death of cancer cells. In conclusion, we identified three pentacyclic triterpenes (1–3) as potent Hh/GLI signaling inhibitors. These compounds showed an important relationship among Hh/GLI signaling inhibition, the decreased expression of the anti-apoptosis protein BCL2, and cytotoxicity against cancer cells. These compounds might become good tools and/or leads to new agents in the investigation of Hh/GLI signaling pathway inhibitors.
    Experimental
    Acknowledgements
    Introduction Acute myeloid leukemia (AML) is a clonal disorder characterized by accumulation of malignant hematopoietic progenitor cells with impaired differentiation program. Despite important progress in the therapy of AML and high rates of complete remission after induction chemotherapy, most patients will relapse and die from the disease. Therefore, new agents or novel drug combinations are needed urgently [1]. The hedgehog (Hh) pathway plays a critical role during development of embryos and cancer including leukemia, lymphoma and multiple myeloma [2], [3], [4], [5], [6]. Recent studies have demonstrated that some inhibitors of this pathway can be used as a cancer therapeutic strategy [7], [8]. Moreover, growing evidence suggest that Gli is more important than smo in the development of cancer [9]. While cyclopamine, a widely used smo inhibitor, has been reported to be effective in B-cell malignancies in vitro and in vivo, its effects on leukemia are not obvious [3], [5]. In chronic lymphocytic leukemia, Gli inhibitor – GANT61 appears to be more powerful than cyclopamine, but its effect on AML is not well documented [10]. The mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers, including AML [11]. Moreover, antileukemic activity of rapamycin, a mTOR inhibitor, in acute myeloid leukemia has been studied in various preclinical models [12], [13]. And inhibition of mTOR or p70S6K2 down-regulates Hh/Gli pathway in non-small cell lung cancer and inhibition of AKT down-regulates Gli in various tumors including anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) [14], [15], [16]. The regulation of rapamycin on Gli in AML and the potential cytotoxic effects of GANT61 in combination with rapamycin have not yet been determined in hematological malignancies.
    Materials and methods
    Results
    Discussion In the current study, we investigated inhibition of Gli activity in AML cells in vitro in order to determine its effect on AML. Previous data have shown that Hh/Gli signaling pathway is involved in AML. Despite smo inhibitor, cyclopamine, showed no obvious cytotoxic effect on AML cells, it is hypothesized that Gli inhibition might be an alternative target for treatment of AML [3]. GANT61 is a new Gli inhibitor which has been used in colon cancer, human bladder transitional carcinoma and chronic lymphocytic leukemia [10], [27], [28]. Our in vitro data showed that in contrast to smo antagonism, Gli inhibition by GANT61 resulted in a massive onset of apoptosis in AML cells. And the specificity of this compound was confirmed by Gli1 siRNA. Gli silencing by siRNA also inhibits growth of other cancers such as Ewing sarcoma family of tumors, brain glioma cell and hepatocellular carcinoma cells, supporting that Gli might be a vital factor for cancer growth [29], [30], [31]. A recent report about CLL is consistent with our results, which shows that inhibition of Gli, but not smo, induces apoptosis in chronic lymphocytic leukemia cells [10]. Therefore GANT61 might be a new choice for treatment of AML. In fact, considering the report that smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma, GANT61 might also be an optimal choice for cancer cells which are insensitive to cyclopamine [32]. Since Gli1, not smo, has been proved to be important to normal hematopoiesis, it is still unknown if GANT61 might damage normal hemapoietic stem cell [33]. This study is now ongoing.