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Tomas Hudlicky - One of the best experts on this subject based on the ideXlab platform.
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Isolation, Synthesis, and Semisynthesis of Amaryllidaceae Constituents from Narcissus and Galanthus sp.: De Novo Total Synthesis of 2- epi-Narciclasine.
Journal of Natural Products, 2018Co-Authors: Suresh Borra, Ringaile Lapinskaite, Christine J. Kempthorne, David K. Liscombe, James Mcnulty, Tomas HudlickyAbstract:An efficient protocol for the isolation of Narciclasine from common Amaryllidaceae bulbs, separation from haemanthamine, and the occurrence of a trace alkaloid, 2-epi-Narciclasine, are reported. Attempts to convert natural Narciclasine to its C-2 epimer by Mitsunobu inversion or oxidation/reduction sequences were compromised by rearrangement and aromatization processes, through which a synthesis of the alkaloid narciprimine was achieved. The methylation of the 7-hydroxy group of natural Narciclasine followed by protection of the 3,4-diol function and oxidation/reduction sequence provided the target C-2 epimer. A de novo chemoenzymatic synthesis of 2-epi-Narciclasine from m-dibromobenzene is also described. Haemanthamine and narciprimine were readily detected in the crude extracts of Narcissus and Galanthus bulbs containing Narciclasine, and the occurrence of 2-epi-Narciclasine as a trace natural product in Galanthus sp. is reported for the first time.
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Isolation, Synthesis, and Semisynthesis of Amaryllidaceae Constituents from Narcissus and Galanthus sp.: De Novo Total Synthesis of 2-epi-Narciclasine
2018Co-Authors: Suresh Borra, Ringaile Lapinskaite, Christine J. Kempthorne, David K. Liscombe, James Mcnulty, Tomas HudlickyAbstract:An efficient protocol for the isolation of Narciclasine from common Amaryllidaceae bulbs, separation from haemanthamine, and the occurrence of a trace alkaloid, 2-epi-Narciclasine, are reported. Attempts to convert natural Narciclasine to its C-2 epimer by Mitsunobu inversion or oxidation/reduction sequences were compromised by rearrangement and aromatization processes, through which a synthesis of the alkaloid narciprimine was achieved. The methylation of the 7-hydroxy group of natural Narciclasine followed by protection of the 3,4-diol function and oxidation/reduction sequence provided the target C-2 epimer. A de novo chemoenzymatic synthesis of 2-epi-Narciclasine from m-dibromobenzene is also described. Haemanthamine and narciprimine were readily detected in the crude extracts of Narcissus and Galanthus bulbs containing Narciclasine, and the occurrence of 2-epi-Narciclasine as a trace natural product in Galanthus sp. is reported for the first time
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synthesis and biological activity of 10 aza Narciclasine
Advanced Synthesis & Catalysis, 2015Co-Authors: Sergey Vshyvenko, Audrey Weber, Natalia Neverova, Bradley John Hedberg, Zemane Wgiorgis, Tomas HudlickyAbstract:The first active aza analogue of Narciclasine was synthesized from a pentasubstituted derivative of nicotinic acid. The key features of the synthesis include a halogen dance of bromopyridine and an intramolecular Heck reaction with a conduramine derived chemoenzymatically from bromobenzene. 10-Aza-Narciclasine was found to have reasonable activity against several cancer cell lines.
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Synthesis and Biological Activity of 10‐Aza‐Narciclasine
Advanced Synthesis & Catalysis, 2014Co-Authors: Sergey Vshyvenko, Zemane W'giorgis, Audrey Weber, Natalia Neverova, Bradley John Hedberg, Tomas HudlickyAbstract:The first active aza analogue of Narciclasine was synthesized from a pentasubstituted derivative of nicotinic acid. The key features of the synthesis include a halogen dance of bromopyridine and an intramolecular Heck reaction with a conduramine derived chemoenzymatically from bromobenzene. 10-Aza-Narciclasine was found to have reasonable activity against several cancer cell lines.
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Synthesis and biological evaluation of unnatural derivatives of Narciclasine: 7-aza-norNarciclasine and its N-oxide.
Bioorganic & medicinal chemistry letters, 2014Co-Authors: Sergey Vshyvenko, Mary R. Reisenauer, Snezna Rogelj, Tomas HudlickyAbstract:Several unnatural derivatives of Narciclasine were prepared in which the C-7 carbon was replaced with nitrogen. The 7-aza derivative and its N-oxide were prepared by the coupling of iodopicolinic acid with a conduramine unit derived chemoenzymatically from bromobenzene. Intramolecular Heck reaction was used to construct the isocarbostyryl ring system. The compounds were submitted to biological screening against cancer cell lines. Full experimental and spectra data are provided for all new compounds.
Bo Han - One of the best experts on this subject based on the ideXlab platform.
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Narciclasine induces autophagy dependent apoptosis in triple negative breast cancer cells by regulating the ampk ulk1 axis
Cell Proliferation, 2018Co-Authors: Chuan Cao, Wei Huang, Nan Zhang, Xiao-li Pan, Cheng Peng, Bo HanAbstract:OBJECTIVES Autophagy and apoptosis are major types of eukaryotic programmed cell death, and regulating these processes holds promise for treating cancers. In this study, we explored the regulation mechanisms of Narciclasine to autophagy and apoptosis processes in triple-negative breast cancer. MATERIALS AND METHODS Effects of Narciclasine on proliferation, apoptosis, and autophagy of HCC-1937 and MDA-MB-231 triple-negative breast cancer (TNBC) cells were assessed using transmission electronic microscopy, flow cytometry following staining with Annexin V-FITC and propidium iodide, RNA sequencing, real-time PCR, and Western blotting. The ability of Narciclasine to inhibit growth of human HCC1937 TNBC xenografts in mice was assessed, and potential mechanisms of inhibition were explored using immunohistochemistry. RESULTS Narciclasine inhibited TNBC cell proliferation and induced autophagy-dependent apoptosis in a dose-dependent manner. These apoptotic effects could be reversed using autophagy inhibitors, including an AMPK inhibitor and ULK1 siRNA. Consistent with these in vitro results, Narciclasine significantly inhibited TNBC tumour growth in mice by upregulating autophagy-dependent apoptosis. CONCLUSIONS Our findings suggest that Narciclasine regulates the AMPK-ULK1 signalling axis to promote autophagy-dependent apoptosis, demonstrating therapeutic potential against TNBC.
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Narciclasine induces autophagy‐dependent apoptosis in triple‐negative breast cancer cells by regulating the AMPK‐ULK1 axis
Cell proliferation, 2018Co-Authors: Chuan Cao, Wei Huang, Nan Zhang, Xiao-li Pan, Cheng Peng, Bo HanAbstract:OBJECTIVES Autophagy and apoptosis are major types of eukaryotic programmed cell death, and regulating these processes holds promise for treating cancers. In this study, we explored the regulation mechanisms of Narciclasine to autophagy and apoptosis processes in triple-negative breast cancer. MATERIALS AND METHODS Effects of Narciclasine on proliferation, apoptosis, and autophagy of HCC-1937 and MDA-MB-231 triple-negative breast cancer (TNBC) cells were assessed using transmission electronic microscopy, flow cytometry following staining with Annexin V-FITC and propidium iodide, RNA sequencing, real-time PCR, and Western blotting. The ability of Narciclasine to inhibit growth of human HCC1937 TNBC xenografts in mice was assessed, and potential mechanisms of inhibition were explored using immunohistochemistry. RESULTS Narciclasine inhibited TNBC cell proliferation and induced autophagy-dependent apoptosis in a dose-dependent manner. These apoptotic effects could be reversed using autophagy inhibitors, including an AMPK inhibitor and ULK1 siRNA. Consistent with these in vitro results, Narciclasine significantly inhibited TNBC tumour growth in mice by upregulating autophagy-dependent apoptosis. CONCLUSIONS Our findings suggest that Narciclasine regulates the AMPK-ULK1 signalling axis to promote autophagy-dependent apoptosis, demonstrating therapeutic potential against TNBC.
Alexander Kornienko - One of the best experts on this subject based on the ideXlab platform.
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Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers.
Medicinal research reviews, 2012Co-Authors: Gwendoline Van Goietsenoven, Florence Lefranc, Antonio Evidente, Véronique Mathieu, Alexander Kornienko, Robert KissAbstract:The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, Narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, Narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of Narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of Narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, Narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of Narciclasine have failed; thus, research efforts are now focused on Narciclasine prodrugs.
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Biological evaluation of structurally diverse amaryllidaceae alkaloids and their synthetic derivatives: discovery of novel leads for anticancer drug design.
Planta medica, 2009Co-Authors: Antonio Evidente, Artem S. Kireev, Aaron R. Jenkins, Anntherese E. Romero, Wim F.a. Steelant, Severine Van Slambrouck, Alexander KornienkoAbstract:Twenty nine Amaryllidaceae alkaloids and their derivatives belonging to five most common groups, including lycorine-, lycorenine-, tazettine-, crinine-, and Narciclasine-types, were evaluated for antiproliferative, apoptosis inducing and antiinvasive activities in vitro. The antiproliferative properties of each test compound are in agreement with those reported in the literature, while the high potency of amarbellisine is reported for the first time. It was also found that with the exception of ungeremine, amarbellisine and hippeastrine, the antiproliferative effect of the potent compounds is apoptosis-mediated. Thus, apoptosis in Jurkat cells was triggered by Narciclasine, Narciclasine tetraacetate, C10b-R-hydroxypancratistatin, cis-dihydroNarciclasine, trans-dihydroNarciclasine, lycorine, 1-O-acetyllycorine, lycorine-2-one, pseudolycorine, and haemanthamine. With the exception of Narciclasine, lycorine and haemanthamine, the apoptosis inducing properties of these compounds are reported for the first time. The collagen type I invasion assay revealed potent antiinvasive properties associated with N-methyllycorine iodide, hippeastrine, clivimine, buphanamine, and Narciclasine tetraacetate, all of which were tested at non-toxic concentrations. The antiinvasive activity of buphanamine is particularly promising since this alkaloid is not toxic to cells even at much higher doses. This work has resulted in identification of several novel leads for anticancer drug design.
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Anticancer evaluation of structurally diverse Amaryllidaceae alkaloids and their synthetic derivatives
Phytochemistry Reviews, 2009Co-Authors: Antonio Evidente, Alexander KornienkoAbstract:Plants of the Amaryllidaceae family have been under intense scrutiny for the presence of the specific metabolites responsible for the medicinal properties associated with them. The study began in 1877 with the isolation of alkaloid lycorine from Narcissus pseudonarcissus and since then more than 100 alkaloids, exhibiting diverse biological activities, have been isolated from the Amaryllidaceae plants. Based on the present scientific evidence, it is likely that isocarbostyril constituents of the Amaryllidaceae, such as Narciclasine, pancratistatin and their congeners, are the most important metabolites responsible for the therapeutic benefits of these plant species in the folk medical treatment of cancer. Notably, Narcissus poeticus L., used by the ancient Greek physicians, is now known to contain about 0.12 g of Narciclasine per kg of fresh bulbs. The focus of the present research work is the chemistry and biology of these compounds as specifically relevant to their potential use in medicine. In particular, the anticancer evaluation of lycorine, Narciclasine as well as of other Amaryllidaceae alkaloids and their synthetic derivatives are presented in this paper. The structure–activity relationships among some groups of Amaryllidaceae alkaloids will be discussed.
Antonio Evidente - One of the best experts on this subject based on the ideXlab platform.
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Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers.
Medicinal research reviews, 2012Co-Authors: Gwendoline Van Goietsenoven, Florence Lefranc, Antonio Evidente, Véronique Mathieu, Alexander Kornienko, Robert KissAbstract:The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, Narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, Narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of Narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of Narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, Narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of Narciclasine have failed; thus, research efforts are now focused on Narciclasine prodrugs.
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Targeting of eEF1A with Amaryllidaceae isocarbostyrils as a strategy to combat melanomas.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2010Co-Authors: Gwendoline Van Goietsenoven, Jenna Hutton, Jean-paul Becker, Benjamin Lallemand, Francis Robert, Florence Lefranc, Christine Pirker, Guy Vandenbussche, Pierre Van Antwerpen, Antonio EvidenteAbstract:Melanomas display poor response rates to adjuvant therapies because of their intrinsic resistance to proapoptotic stimuli. This study indicates that such resistance can be overcome, at least partly, through the targeting of eEF1A elongation factor with Narciclasine, an Amaryllidaceae isocarbostyril controlling plant growth. Narciclasine displays IC(50) growth inhibitory values between 30-100 nM in melanoma cell lines, irrespective of their levels of resistance to proapoptotic stimuli. Normal noncancerous cell lines are much less affected. At nontoxic doses, Narciclasine also significantly improves (P=0.004) the survival of mice bearing metastatic apoptosis-resistant melanoma xenografts in their brain. The eEF1A targeting with Narciclasine (50 nM) leads to 1) marked actin cytoskeleton disorganization, resulting in cytokinesis impairment, and 2) protein synthesis impairment (elongation and initiation steps), whereas apoptosis is induced at higher doses only (≥200 nM). In addition to molecular docking validation and identification of potential binding sites, we biochemically confirmed that Narciclasine directly binds to human recombinant and yeast-purified eEF1A in a nanomolar range, but not to actin or elongation factor 2, and that 5 nM Narciclasine is sufficient to impair eEF1A-related actin bundling activity. eEF1A is thus a potential target to combat melanomas regardless of their apoptosis-sensitivity, and this finding reconciles the pleiotropic cytostatic of Narciclasine. -
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Targeting of eEF1A with Amaryllidaceae isocarbostyrils as a strategy to combat melanomas
'FASEB', 2010Co-Authors: Gwendoline Van Goietsenoven, Jenna Hutton, Jean-paul Becker, Benjamin Lallemand, Francis Robert, Florence Lefranc, Christine Pirker, Guy Vandenbussche, Pierre Van Antwerpen, Antonio EvidenteAbstract:Melanomas display poor response rates to adjuvant therapies because of their intrinsic resistance to proapoptotic stimuli. This study indicates that such resistance can be overcome, at least partly, through the targeting of eEF1A elongation factor with Narciclasine, an Amaryllidaceae isocarbostyril controlling plant growth. Narciclasine displays IC50 growth inhibitory values between 30–100 nM in melanoma cell lines, irrespective of their levels of resistance to proapoptotic stimuli. Normal noncancerous cell lines are much less affected. At nontoxic doses, Narciclasine also significantly improves (P=0.004) the survival of mice bearing metastatic apoptosis-resistant melanoma xenografts in their brain. The eEF1A targeting with Narciclasine (50 nM) leads to 1) marked actin cytoskeleton disorganization, resulting in cytokinesis impairment, and 2) protein synthesis impairment (elongation and initiation steps), whereas apoptosis is induced at higher doses only (200 nM). In addition to molecular docking validation and identification of potential binding sites, we biochemically confirmed that Narciclasine directly binds to human recombinant and yeast-purified eEF1A in a nanomolar range, but not to actin or elongation factor 2, and that 5 nM Narciclasine is sufficient to impair eEF1A-related actin bundling activity. eEF1A is thus a potential target to combat melanomas regardless of their apoptosis-sensitivity, and this finding reconciles the pleiotropic cytostatic of narciclasin
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Biological evaluation of structurally diverse amaryllidaceae alkaloids and their synthetic derivatives: discovery of novel leads for anticancer drug design.
Planta medica, 2009Co-Authors: Antonio Evidente, Artem S. Kireev, Aaron R. Jenkins, Anntherese E. Romero, Wim F.a. Steelant, Severine Van Slambrouck, Alexander KornienkoAbstract:Twenty nine Amaryllidaceae alkaloids and their derivatives belonging to five most common groups, including lycorine-, lycorenine-, tazettine-, crinine-, and Narciclasine-types, were evaluated for antiproliferative, apoptosis inducing and antiinvasive activities in vitro. The antiproliferative properties of each test compound are in agreement with those reported in the literature, while the high potency of amarbellisine is reported for the first time. It was also found that with the exception of ungeremine, amarbellisine and hippeastrine, the antiproliferative effect of the potent compounds is apoptosis-mediated. Thus, apoptosis in Jurkat cells was triggered by Narciclasine, Narciclasine tetraacetate, C10b-R-hydroxypancratistatin, cis-dihydroNarciclasine, trans-dihydroNarciclasine, lycorine, 1-O-acetyllycorine, lycorine-2-one, pseudolycorine, and haemanthamine. With the exception of Narciclasine, lycorine and haemanthamine, the apoptosis inducing properties of these compounds are reported for the first time. The collagen type I invasion assay revealed potent antiinvasive properties associated with N-methyllycorine iodide, hippeastrine, clivimine, buphanamine, and Narciclasine tetraacetate, all of which were tested at non-toxic concentrations. The antiinvasive activity of buphanamine is particularly promising since this alkaloid is not toxic to cells even at much higher doses. This work has resulted in identification of several novel leads for anticancer drug design.
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Anticancer evaluation of structurally diverse Amaryllidaceae alkaloids and their synthetic derivatives
Phytochemistry Reviews, 2009Co-Authors: Antonio Evidente, Alexander KornienkoAbstract:Plants of the Amaryllidaceae family have been under intense scrutiny for the presence of the specific metabolites responsible for the medicinal properties associated with them. The study began in 1877 with the isolation of alkaloid lycorine from Narcissus pseudonarcissus and since then more than 100 alkaloids, exhibiting diverse biological activities, have been isolated from the Amaryllidaceae plants. Based on the present scientific evidence, it is likely that isocarbostyril constituents of the Amaryllidaceae, such as Narciclasine, pancratistatin and their congeners, are the most important metabolites responsible for the therapeutic benefits of these plant species in the folk medical treatment of cancer. Notably, Narcissus poeticus L., used by the ancient Greek physicians, is now known to contain about 0.12 g of Narciclasine per kg of fresh bulbs. The focus of the present research work is the chemistry and biology of these compounds as specifically relevant to their potential use in medicine. In particular, the anticancer evaluation of lycorine, Narciclasine as well as of other Amaryllidaceae alkaloids and their synthetic derivatives are presented in this paper. The structure–activity relationships among some groups of Amaryllidaceae alkaloids will be discussed.
Chuan Cao - One of the best experts on this subject based on the ideXlab platform.
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Narciclasine induces autophagy dependent apoptosis in triple negative breast cancer cells by regulating the ampk ulk1 axis
Cell Proliferation, 2018Co-Authors: Chuan Cao, Wei Huang, Nan Zhang, Xiao-li Pan, Cheng Peng, Bo HanAbstract:OBJECTIVES Autophagy and apoptosis are major types of eukaryotic programmed cell death, and regulating these processes holds promise for treating cancers. In this study, we explored the regulation mechanisms of Narciclasine to autophagy and apoptosis processes in triple-negative breast cancer. MATERIALS AND METHODS Effects of Narciclasine on proliferation, apoptosis, and autophagy of HCC-1937 and MDA-MB-231 triple-negative breast cancer (TNBC) cells were assessed using transmission electronic microscopy, flow cytometry following staining with Annexin V-FITC and propidium iodide, RNA sequencing, real-time PCR, and Western blotting. The ability of Narciclasine to inhibit growth of human HCC1937 TNBC xenografts in mice was assessed, and potential mechanisms of inhibition were explored using immunohistochemistry. RESULTS Narciclasine inhibited TNBC cell proliferation and induced autophagy-dependent apoptosis in a dose-dependent manner. These apoptotic effects could be reversed using autophagy inhibitors, including an AMPK inhibitor and ULK1 siRNA. Consistent with these in vitro results, Narciclasine significantly inhibited TNBC tumour growth in mice by upregulating autophagy-dependent apoptosis. CONCLUSIONS Our findings suggest that Narciclasine regulates the AMPK-ULK1 signalling axis to promote autophagy-dependent apoptosis, demonstrating therapeutic potential against TNBC.
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Narciclasine induces autophagy‐dependent apoptosis in triple‐negative breast cancer cells by regulating the AMPK‐ULK1 axis
Cell proliferation, 2018Co-Authors: Chuan Cao, Wei Huang, Nan Zhang, Xiao-li Pan, Cheng Peng, Bo HanAbstract:OBJECTIVES Autophagy and apoptosis are major types of eukaryotic programmed cell death, and regulating these processes holds promise for treating cancers. In this study, we explored the regulation mechanisms of Narciclasine to autophagy and apoptosis processes in triple-negative breast cancer. MATERIALS AND METHODS Effects of Narciclasine on proliferation, apoptosis, and autophagy of HCC-1937 and MDA-MB-231 triple-negative breast cancer (TNBC) cells were assessed using transmission electronic microscopy, flow cytometry following staining with Annexin V-FITC and propidium iodide, RNA sequencing, real-time PCR, and Western blotting. The ability of Narciclasine to inhibit growth of human HCC1937 TNBC xenografts in mice was assessed, and potential mechanisms of inhibition were explored using immunohistochemistry. RESULTS Narciclasine inhibited TNBC cell proliferation and induced autophagy-dependent apoptosis in a dose-dependent manner. These apoptotic effects could be reversed using autophagy inhibitors, including an AMPK inhibitor and ULK1 siRNA. Consistent with these in vitro results, Narciclasine significantly inhibited TNBC tumour growth in mice by upregulating autophagy-dependent apoptosis. CONCLUSIONS Our findings suggest that Narciclasine regulates the AMPK-ULK1 signalling axis to promote autophagy-dependent apoptosis, demonstrating therapeutic potential against TNBC.
