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Bruceantin inhibits multiple myeloma cancer stem cell proliferation.

ABSTRACT: Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the ?-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM.

SUBMITTER: Issa ME

PROVIDER: S-EPMC5036415 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Bruceantin inhibits multiple myeloma cancer stem cell proliferation.

Issa Mark E ME Berndt Sarah S Carpentier Gilles G Pezzuto John M JM Cuendet Muriel M

Cancer biology & therapy 20160719 9

Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8 ...[more]

PMID: 27434731

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Project description:Multiple myeloma (MM) is a hematological cancer causing from accumulated abnormal plasma cells. STAT3 overexpression in MM appears to be mediated by a variety of factors, and it may be associated with an adverse prognosis and play a role in microenvironment-dependent treatment resistance. Unfortunately, MM remains an incurable disease, as relapse is very common. Therefore, there is urgent need to develop new treatment options for MM. Radotinib is a novel anti-cancer drug, currently approved in South Korea for the treatment of chronic myeloid leukemia patients. It is an oral, multitargeted inhibitor of receptor tyrosine kinases, including BCR-ABL, c-KIT, PDGFR, and Src family kinases. However, little is known about the effects of radotinib on multiple myeloma cells. However, little is known about the effects of radotinib on multiple myeloma cells. But even tinip almost not known about the impact of multiple myeloma cells. Moreover, nothing is known about how it affects STAT3 and JAK2. In this study, we analyzed the effect of radotinib on multiple myeloma cells. Herein, Moreover, nothing is known about how it. Moreover, not all is known about how the affects STAT3 and JAK2. We investigated the effect of radotinib on the STAT3 signaling pathway in MM cells, including several MM cell lines and mouse models. So we investigated the effect of radotinib on MM cells, including several MM cell lines and mouse models. Interestingly, radotinib induced apoptosis, and inhibited cell proliferation in MM cells including RPMI-8226, MM.1S, U266B1, and IM-9 cells. Moreover, radotinib treatment significantly increased the number Annexin V-positive cells and G0/G1-phase cells. In addition, radotinib treatment in various MM cells strongly suppressed the activity and expression of STAT3 and JAK2 proteins. We also observed that diverse proteins related to the STAT3 signaling pathway, including c-Myc, Bcl-xL, Mcl-1, cyclin D1 and cyclin D3, were powerfully inhibited by radotinib treatment in MM cells. Furthermore, radotinib significantly suppressed MM cell growth in a xenograft animal model using IM-9 cells. In conclusion, radotinib may play an important role as a candidate agent for MM treatment.

Project description:The present study aimed to explore the regulatory role of sirtuin 2 (SIRT2) in malignant progression of multiple myeloma (MM) and the potential associated signaling pathways. In total, 30 patients with MM and 15 healthy bone marrow donors were enrolled in the current study and their bone marrow samples were collected to isolate the plasma cells. The expression levels of SIRT2 were detected in MM cell lines (KMS‑28BM, U266, RPMI‑8226 and NCI‑H929) and normal plasma cells (collected from healthy bone marrow donors as the control) via reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis. SIRT2 knockdown was established by transfecting two MM cell lines (RPMI‑8226 and NCI‑H929 cells) with short hairpin RNA‑SIRT2 recombinant plasmid; the control group was transfected with a control recombinant plasmid. Subsequently, the effect of SIRT2 knockdown on MM cell proliferation, apoptosis, cell cycle progression and RAS/ERK signaling was investigated via Cell Counting Kit‑8, flow cytometry, RT‑qPCR and western blot assays, respectively. The mRNA and protein expression levels of SIRT2 were increased in U266 (P<0.001), KMS‑28BM (P<0.001), RPMI‑8226 (P<0.001) and NCI‑H929 (P<0.001) cells compared with those in the control cells. In NCI‑H929 and RPMI‑8226 cells, cell proliferation was decreased 48 h (P<0.05) and 72 h (P<0.05) after SIRT2 knockdown. Furthermore, the cell apoptotic rate was elevated 48 h after SIRT2 knockdown (P<0.01). In addition, the percentage of cells at the G0/G1 phase was increased (P<0.01), whereas the percentage of cells at the S phase was reduced (P<0.01) 48 h after SIRT2 knockdown. The expression levels of HRAS and phosphorylated‑ERK were also reduced 48 h after SIRT2 knockdown. In conclusion, SIRT2 was highly expressed in MM cell lines, and knockdown of SIRT2 inhibited MM cell proliferation, inactivated the RAS/ERK signaling pathway, and promoted cell apoptosis and cell cycle arrest.

Project description:BackgroundData are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma.MethodsBetween April 2005 and July 2009, we randomly assigned 460 patients who were younger than 71 years of age and had stable disease or a marginal, partial, or complete response 100 days after undergoing stem-cell transplantation to lenalidomide or placebo, which was administered until disease progression. The starting dose of lenalidomide was 10 mg per day (range, 5 to 15).ResultsThe study-drug assignments were unblinded in 2009, when a planned interim analysis showed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P<0.001); of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 86 of 231 patients who received lenalidomide (37%) and 132 of 229 patients who received placebo (58%) had disease progression or had died. The median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). A total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) died (P=0.03). More grade 3 or 4 hematologic adverse events and grade 3 nonhematologic adverse events occurred in patients who received lenalidomide (P<0.001 for both comparisons). Second primary cancers occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%).ConclusionsLenalidomide maintenance therapy, initiated at day 100 after hematopoietic stem-cell transplantation, was associated with more toxicity and second cancers but a significantly longer time to disease progression and significantly improved overall survival among patients with myeloma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00114101.).

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Bruceantin inhibits multiple myeloma cancer stem cell proliferation.

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Bruceantin inhibits multiple myeloma cancer stem cell proliferation.

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