The hedgehog inhibitor cyclopamine induces apoptosis in leukemic cells<i>in vitro</i>

Warzecha, J.; Bonke, Leonie; Koehl, Ulrike; Munkelt, Doreen; Göttig, Stephan; Percic, D.; Arabmotlagh, Mohammad; Kurth, Andreas

doi:10.1080/10428190802510315

Cited by 12 publications

(10 citation statements)

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“…Autocrine signaling in which tumor cells both secrete and respond to ligand has also been described in a wide variety of human solid tumors [11], [14]–[16], [41]–[43]. In addition, recent data have suggested that paracrine Hh signaling may mediate interactions between tumor cells and non-transformed stromal cells through multiple mechanisms [5], [26], [41], [42]. In NHL and MM, stromal cells have been found to secrete HH ligand that promotes the survival of malignant plasma cells [8].…”

Section: Discussionmentioning

confidence: 99%

“…Preliminary reports also suggest that Hedgehog signaling promotes the growth of T-ALL [3], [4]. The role of developmental signaling pathways in the pathogenesis and self-renewal of B cell ALL (B-ALL) is not clear, but recent data suggest that the Hh signaling pathway is involved in the development of B cell precursors from primitive hematopoietic stem cells, as well as self-renewal and cell survival in human B cell malignancies [5]–[8].…”

Section: Introductionmentioning

confidence: 99%

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Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926

et al. 2010

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Conserved embryonic signaling pathways such as Hedgehog (Hh), Wingless and Notch have been implicated in the pathogenesis of several malignancies. Recent data suggests that Hh signaling plays a role in normal B-cell development, and we hypothesized that Hh signaling may be important in precursor B-cell acute lymphocytic leukemia (B-ALL). We found that the expression of Hh pathway components was common in human B-ALL cell lines and clinical samples. Moreover, pathway activity could be modulated by Hh ligand or several pathway inhibitors including cyclopamine and the novel SMOOTHENED (SMO) inhibitor IPI-926. The inhibition of pathway activity primarily impacted highly clonogenic B-ALL cells expressing aldehyde dehydrogenase (ALDH) by limiting their self-renewal potential both in vitro and in vivo. These data demonstrate that Hh pathway activation is common in B-ALL and represents a novel therapeutic target regulating self-renewal and persistence of the malignant clone.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926

et al. 2010

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“…16 The Hh pathway inhibitor cyclopamine can induce cell death of leukemia cells in vitro. 17 Inhibition of Hh pathway could reduce drug resistance of CD34 C leukemia cells in vitro. 18 Therefore, the combination of Hh pathway inhibitors and TKIs might represent a hopeful strategy for improving treatment outcomes of patients with CML.…”

Section: Introductionmentioning

confidence: 99%

Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia

Zeng

Zhao

et al. 2015

Autophagy

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The frontline tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, drug resistance is the major clinical challenge in the treatment of CML. The Hedgehog (Hh) signaling pathway and autophagy are both related to tumorigenesis, cancer therapy, and drug resistance. This study was conducted to explore whether the Hh pathway could regulate autophagy in CML cells and whether simultaneously regulating the Hh pathway and autophagy could induce cell death of drug-sensitive or -resistant BCR-ABL(+) CML cells. Our results indicated that pharmacological or genetic inhibition of Hh pathway could markedly induce autophagy in BCR-ABL(+) CML cells. Autophagic inhibitors or ATG5 and ATG7 silencing could significantly enhance CML cell death induced by Hh pathway suppression. Based on the above findings, our study demonstrated that simultaneously inhibiting the Hh pathway and autophagy could markedly reduce cell viability and induce apoptosis of imatinib-sensitive or -resistant BCR-ABL(+) cells. Moreover, this combination had little cytotoxicity in human peripheral blood mononuclear cells (PBMCs). Furthermore, this combined strategy was related to PARP cleavage, CASP3 and CASP9 cleavage, and inhibition of the BCR-ABL oncoprotein. In conclusion, this study indicated that simultaneously inhibiting the Hh pathway and autophagy could potently kill imatinib-sensitive or -resistant BCR-ABL(+) cells, providing a novel concept that simultaneously inhibiting the Hh pathway and autophagy might be a potent new strategy to overcome CML drug resistance.

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“…Besides BCC, Hh signaling is also activated in other malignancies such as medulloblastoma,30,31 colon,32 prostate,33,34 breast,35 lung,36 and various hematologic malignancies 37–40. The Hh pathway dependent gene upregulation leads to increased cell proliferation and cell survival, and promotes bone metastases 41.…”

Section: Hh Pathway and Its Role In Bccmentioning

confidence: 99%

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma

Macha¹,

Batra²,

Ganti³

2013

CMAR

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Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC.

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The hedgehog inhibitor cyclopamine induces apoptosis in leukemic cellsin vitro

Cited by 12 publications

References 11 publications

Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926

Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926

Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma

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