Cyclopamine tartrate, a modulator of hedgehog signaling and mitochondrial respiration, effectively arrests lung tumor growth and progression

Kalainayakan, Sarada Preeta; Ghosh, Poorva; Dey, Sanchareeka; FitzGerald, Keely E.; Sohoni, Sagar; Konduri, Purna Chaitanya; Garrossian, Massoud; Liu, Li; Li, Zhang

doi:10.1038/s41598-018-38345-1

Cited by 21 publications

(24 citation statements)

References 88 publications

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“…ROS-mediated dimerization of Bax, a pro-apoptotic member of the Bcl-2 protein family, and oxidation of cardiolipin trigger the release of cytochrome c into the cytosol, and has been proposed as oxidative stress-based mechanisms of apoptotic activation [ 117 ]. Another naturally occurring compound, cyclopamine, inhibits hedgehog signaling and induces apoptosis in AML CD34 + blasts [ 114 ], and directly inhibits OxPhos in lung tumors [ 118 ]. Avocatin B induces ROS-dependent, mitochondria-mediated apoptosis in AML cells, as well as inhibits fatty acid oxidation.…”

Section: Modulation Of Mitochondrial Ros As Aml Treatment Strategymentioning

confidence: 99%

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

2021

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Acute myeloid leukemias (AML) are a group of aggressive hematologic malignancies resulting from acquired genetic mutations in hematopoietic stem cells that affect patients of all ages. Despite decades of research, standard chemotherapy still remains ineffective for some AML subtypes and is often inappropriate for older patients or those with comorbidities. Recently, a number of studies have identified unique mitochondrial alterations that lead to metabolic vulnerabilities in AML cells that may present viable treatment targets. These include mtDNA, dependency on oxidative phosphorylation, mitochondrial metabolism, and pro-survival signaling, as well as reactive oxygen species generation and mitochondrial dynamics. Moreover, some mitochondria-targeting chemotherapeutics and their combinations with other compounds have been FDA-approved for AML treatment. Here, we review recent studies that illuminate the effects of drugs and synergistic drug combinations that target diverse biomolecules and metabolic pathways related to mitochondria and their promise in experimental studies, clinical trials, and existing chemotherapeutic regimens.

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Section: Modulation Of Mitochondrial Ros As Aml Treatment Strategymentioning

confidence: 99%

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

2021

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“…These are consistent with current findings. For example, according to Kalainayakan et al (2019), cyclopamine tartrate suppresses tumor growth in the lung by inhibiting heme metabolism and OXPHOS (oxidative phosphorylation). A hallmark of cancer is the ability of malignant cells to evade apoptosis (Hanahan and Weinberg, 2011).…”

Section: System Analysis Survival-related Biomarker Gene Sets In 12 Dmentioning

confidence: 99%

Detecting Cancer Survival Related Gene Markers Based on Rectified Factor Network

Liu

Wang

et al. 2020

Front. Bioeng. Biotechnol.

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Detecting gene sets that serve as biomarkers for differentiating patient survival groups may help diagnose diseases robustly and develop multi-gene targeted therapies. However, due to the exponential growth of search space imposed by gene combinations, the performance of existing methods is still far from satisfactory. In this study, we developed a new method called BISG (BIclustering based Survival-related Gene sets detection) based on a rectified factor network (RFN) model, which allows efficiently biclustering gene subsets. By correlating genes in each significant bicluster with patient survival outcomes using a log-rank test and multi-sampling strategy, multiple survival-related gene sets can be detected. We applied BISG on three different cancer types, and the resulting gene sets were tested as biomarkers for survival analyses. Secondly, we systematically analyzed 12 different cancer datasets. Our analysis shows that the genes in all the survival-related gene sets are mainly from five gene families: microRNA protein coding host genes, zinc fingers C2H2-type, solute carriers, CD (cluster of differentiation) molecules, and ankyrin repeat domain containing genes. Moreover, we found that they are mainly enriched in heme metabolism, apoptosis, hypoxia and inflammatory response-related pathways. We compared BISG with two other methods, GSAS and IPSOV. Results show that BISG can better differentiate patient survival groups in different datasets. The identified biomarkers suggested by our study provide useful hypotheses for further investigation. BISG is publicly available with open source at https:// github.com/LingtaoSu/BISG.

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“…As mTOR is the main regulator for mitochondrial metabolism, the synergistic inhibition of mTOR signalling through cyclopamine and rapamycin affects the oxidative phosphorylation in mitochondria. Nevertheless, it is possible that cyclopamine influences oxidative phosphorylation independently from the canonical Hh signalling pathway, as it was postulated by Kalainayakan et al in 2019 [ 45 ]. This assumption is supported by the fact that no significant changes were observed in the gene expression of Gli1 and Ptch1 after exposure to cyclopamine.…”

Section: Discussionmentioning

confidence: 99%

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

Spormann

Rennert

Kolbe

et al. 2020

Cells

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In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between mTOR and Hh signalling was previously demonstrated in cancer development and progression, knowledge of their molecular crosstalk in healthy liver is lacking. To close this information gap, we used a transgenic mouse model, which allows hepatocyte-specific deletion of the Hh pathway, and in vitro studies to reveal interactions between Hh and mTOR signalling. The study was conducted in male and female mice to investigate sexual differences in the crosstalk of these signalling pathways. Our results reveal that the conditional Hh knockout reduces mitochondrial adenosine triphosphate (ATP) production in primary hepatocytes from female mice and inhibits autophagy in hepatocytes from both sexes. Furthermore, in vitro studies show a synergistic effect of cyclopamine and rapamycin on the inhibition of mTor signalling and oxidative respiration in primary hepatocytes from male and female C57BL/6N mice. Overall, our results demonstrate that the impairment of Hh signalling influences mTOR signalling and therefore represses oxidative phosphorylation and autophagy.

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Cyclopamine tartrate, a modulator of hedgehog signaling and mitochondrial respiration, effectively arrests lung tumor growth and progression

Cited by 21 publications

References 88 publications

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

Mitochondrial metabolism as a target for acute myeloid leukemia treatment

Detecting Cancer Survival Related Gene Markers Based on Rectified Factor Network

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

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