Bersavine: A Novel Bisbenzylisoquinoline Alkaloid with Cytotoxic, Antiproliferative and Apoptosis-Inducing Effects on Human Leukemic Cells

Bersavine is the new bisbenzylisoquinoline alkaloid isolated from the Berberis vulgaris L. (Berberidaceae) plant. The results of cytotoxicity screening 48 h post-treatment showed that bersavine considerably inhibits the proliferation and viability of leukemic (Jurkat, MOLT-4), colon (HT-29), cervix (HeLa) and breast (MCF-7) cancer cells with IC50 values ranging from 8.1 to 11 µM. The viability and proliferation of leukemic Jurkat and MOLT-4 cells were decreased after bersavine treatment in a time- and dose-dependent manner. Bersavine manifested concentration-dependent antiproliferative activity in human lung, breast, ovarian and hepatocellular carcinoma cell lines using a xCELLigence assay. Significantly higher percentages of MOLT-4 cells exposed to bersavine at 20 µM for 24 h were arrested in the G1 phase of the cell cycle using the flow cytometry method. The higher percentage of apoptotic cells was measured after 24 h of bersavine treatment. The upregulation of p53 phosphorylated on Ser392 was detected during the progression of MOLT-4 cell apoptosis. Mechanistically, bersavine-induced apoptosis is an effect of increased activity of caspases, while reduced proliferation seems dependent on increased Chk1 Ser345 phosphorylation and decreased Rb Ser807/811 phosphorylation in human leukemic cells.

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Novel vitamin D3 analog, 21-(3-methyl-3-hydroxy-butyl)-19-nor D3, that modulates cell growth, differentiation, apoptosis, cell cycle, and induction of PTEN in leukemic cells

Blood ◽

10.1182/blood.v97.8.2427 ◽

2001 ◽

Vol 97 (8) ◽

pp. 2427-2433 ◽

Cited By ~ 48

Author(s):

Jun-ichi Hisatake ◽

James O'Kelly ◽

Milan R. Uskokovic ◽

Shigeru Tomoyasu ◽

H. Phillip Koeffler

Keyword(s):

Cancer Cells ◽

Vitamin D3 ◽

Active Form ◽

Annexin V ◽

Pten Expression ◽

Leukemic Cells ◽

Side Chains ◽

Dependent Manner ◽

Dose Dependent ◽

Mcf 7

Abstract The active form of vitamin D3, 1,25(OH)2D3, inhibits proliferation and induces differentiation of a variety of malignant cells. A new class of vitamin D3 analogs, having 2 identical side chains attached to carbon-20, was synthesized and the anticancer effects evaluated. Four analogs were evaluated for their ability to inhibit growth of myeloid leukemia (NB4, HL-60), breast (MCF-7), and prostate (LNCaP) cancer cells. All 4 analogs inhibited growth in a dose-dependent manner. Most effective was 21-(3-methyl-3-hydroxy-butyl)-19-nor D3(Gemini-19-nor), which has 2 side chains and removal of the C-19. Gemini-19-nor was approximately 40 625-, 70-, 23-, and 380-fold more potent than 1,25(OH)2D3 in inhibiting 50% clonal growth (ED50) of NB4, HL-60, MCF-7, and LNCaP cells, respectively. Gemini-19-nor (10−8 M) strongly induced expression of CD11b and CD14 on HL-60 cells (90%); in contrast, 1,25(OH)2D3 (10−8 M) stimulated only 50% expression. Annexin V assay showed that Gemini-19-nor and 1,25(OH)2D3 induced apoptosis in a dose-dependent fashion. Gemini-19-nor (10−8 M, 4 days) caused apoptosis in approximately 20% of cells, whereas 1,25(OH)2D3 at the same concentration did not induce apoptosis. Gemini-19-nor increased in HL-60 both the proportion of cells in the G1/G0 phase and expression level of p27kip1. Moreover, Gemini-19-nor stimulated expression of the potential tumor suppressor, PTEN. Furthermore, other inducers of differentiation, all-trans-retinoic acid and 12-O-tetradecanoylphorbol 13-acetate, increased PTEN expression in HL-60. In summary, Gemini-19-nor strongly inhibited clonal proliferation in various types of cancer cells, especially NB4 cells, suggesting that further studies to explore its anticancer potential are warranted. In addition, PTEN expression appears to parallel terminal differentiation of myeloid cells.

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Disruption of Leukemia/Stroma Cell Interactions by CXCR4 Antagonist CTCE-9908 Enhances Chemotherapy-Induced Apoptosis in AML

Blood ◽

10.1182/blood.v112.11.2415.2415 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2415-2415

Author(s):

Hongbo Lu ◽

Zhihong Zeng ◽

Yuexi Shi ◽

Sergej Konoplev ◽

Donald Wong ◽

...

Keyword(s):

Bone Marrow ◽

Stromal Cells ◽

Leukemia Cell ◽

Bone Marrow Microenvironment ◽

Cell Interactions ◽

Leukemic Cells ◽

Dependent Manner ◽

Induced Apoptosis ◽

Dose Dependent

Abstract The chemokine receptor CXCR4 is critically involved in the migration of hematopoietic cells towards the stromal derived factor (SDF-1α)-producing bone marrow microenvironment. We and others have previously demonstrated that stroma/leukemia interactions mediate protection of leukemic cells from chemotherapy-induced apoptosis (Konopleva, Leukemia 2002). Using a peptide analog of SDF-1α designated CTCE-9908, we tested the hypothesis that CXCR4 inhibition interferes with stromal/leukemia cell interactions resulting in increased sensitivity to chemotherapy. Our results showed that CTCE-9908 significantly inhibits SDF-1α-induced migration of U937 (43% inhibition) and OCI-AML3 cells (40% inhibition) in a dose-dependent manner. In three of the four primary AML samples which expressed CXCR4 on cell surface and migrated in response to SDF-1α, 50 μg/ml CTCE-9908 reduced SDF-1α-induced migration of leukemic blasts (60%, 19% and 50% inhibition respectively). In in vitro co-culture systems, stromal cells significantly protected OCI-AML3 cells from chemotherapy induced apoptosis [no MS-5, 75.2±5.2% annexinV(+); with MS-5, 59±1.1% annexinV(+)]. Western blot analysis revealed that CTCE-9908 inhibits Akt and Erk phosphorylation in a dose-dependent manner in the OCI-AML3 cell line stimulated by SDF-1α. Blockade of CXCR4 expression with CTCE-9908 markedly abrogated the protective effects of stromal cells on OCI-AML3 [Ara-C, 59±1.1% annexinV(+); Ara-C + CTCE-9908, 76.9±1.35 annexinV(+)]. Most importantly, it decreased stroma-mediated protection from AraC-induced apoptosis in four out of five primary AML samples with surface expression of functional CXCR4 (mean increase, 25.1±9.3% compared to chemotherapy alone). In vivo, subcutaneous administration of 1.25mg CTCE-9908 induced mobilization of leukemic cells from primary AML patient transplanted into NOD/Scid-IL2Rγ-KO mice (from 15% to 27% circulating leukemic cells 1 hour post CTCE-9908 injection). Taken together, our data suggest that SDF-1α/CXCR4 interactions contribute to the resistance of leukemic cells to chemotherapy-induced apoptosis via retention of leukemic cells in the bone marrow microenvironment niches. Disruption of these interactions by the potent CXCR4 inhibitor CTCE-9908 represents a novel strategy for targeting leukemia cell/bone marrow microenvironment interaction. Based on these observations, in vivo experiments are ongoing to characterize the efficacy of chemotherapy combined with CTCE-9908.

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Prognostic Impact and Targeting of CRM1 in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v120.21.870.870 ◽

2012 ◽

Vol 120 (21) ◽

pp. 870-870

Author(s):

Kensuke Kojima ◽

Steven M. Kornblau ◽

Vivian Ruvolo ◽

Seshagiri Duvvuri ◽

Richard E Davis ◽

...

Keyword(s):

Nuclear Export ◽

Annexin V ◽

Dependent Manner ◽

Apoptosis Induction ◽

Wild Type ◽

Ic50 Values ◽

P53 Status ◽

Induced Apoptosis ◽

Dose Dependent ◽

Mdm2 Inhibitor

Abstract Abstract 870 p53 is a transcription factor that prevents abnormal cell growth. Cellular levels of p53 are critically regulated by MDM2, which is frequently over-expressed in AML. Nutlin-3a disrupts MDM2-p53 interaction, increases cellular levels of p53 in both nucleus and cytoplasm, and activates p53 signaling in cells. p53 status is the major determinant of response to MDM2 inhibitors. p53 is shuttled between the nucleus and the cytoplasm, and CRM1 mediates its nuclear export. Karyopharm Therapeutics has developed novel, potent and irreversible small molecule selective inhibitors of CRM1. We hypothesized that CRM1 inhibition would enhance the nuclear activity of p53, thereby enhancing p53-mediated transcription-dependent apoptotic signaling in AML. We measured CRM1 expression in primary AML samples and investigated if blockade of nuclear export of p53 by CRM1 inhibition would enhance MDM2 inhibitor-induced apoptosis in AML. CRM1 expression was investigated in 511 patient AML samples using a validated robust reverse-phase protein array. Higher levels of CRM1 were associated with higher marrow and peripheral blast percentages (P < 0.00001). Expression was lower in those with favorable cytogenetics compared to those with intermediate or unfavorable cytogenetics (P = 0.029). CRM1 levels were higher in patients with FLT3 mutations (P = 0.003). In 3-way correlation (using distance weighted least squares), there was a clear interaction with p53 levels being highest when CRM1 was high and MDM2 levels were low. Overall survival progressively worsened as CRM1 levels increased, with median survival of 66 weeks for those with CRM1 expression in the lowest third, 47 weeks for middle third and 37 weeks in the highest third (P = 0.007). CRM1 levels did not affect remission duration (P = 0.33). The CRM1 inhibitor KPT-185 exhibited dose-dependent anti-proliferative and cytotoxic activity in AML cell lines, as evidenced by low IC50 values and high Annexin V positivity (= low ED50 values). IC50 values for wild-type p53 cells ranged from 27 to 38 nM, and for mutant p53 cells from 48 to 112 nM, suggesting that KPT-185 potently inhibits AML cell growth largely independent of p53. In contrast, apoptosis induction by KPT-185 was much more prominent in p53 wild-type than in p53-defective cells: ED50 values for Annexin V induction were 150, 90 and 85 nM in p53 wild-type and > 1000 nM in 5 of 6 p53 mutant cell lines. Stable p53 knockdown (> 90% efficiency) rendered AML cells resistant to KPT-induced apoptosis. KPT-185 induced p53 target genes TP53I3, GDF15, MDM2 and ZMAT3 partially in a p53-dependent manner. Hence, p53 was identified as major determinant of CRM1 inhibition-induced apoptosis in AML. MDM2-inhibitor Nutlin-3a induced p53 in both nucleus and cytoplasm, while CRM1 inhibition accumulated p53 in the nucleus. Treatment with KPT-185 or Nutlin-3a caused time-dependent increase in cellular p53 levels. The KPT-185/Nutlin-3a combination induced p53 more efficiently than the individual agents by accumulating p53 exclusively in the nucleus, and synergistically induced apoptosis and cell death. p53 knockdown abrogated these synergistic effects. In primary AML cells, both KPT-185 (24.7 – 36.7% Annexin V) and Nutlin-3a (13.6 – 59.8%) induced apoptosis in a dose-dependent manner. Importantly, both KPT-185 and Nutlin-3a induced apoptosis in CD34+CD38- progenitor cell populations as effectively as they did in bulk AML cells, suggesting high sensitivity of CD34+CD38- cells to CRM1 inhibition and MDM2 inhibition. KPT-185 and Nutlin-3a synergized in the induction of apoptosis in both bulk and CD34+CD38- AML progenitor cells: combination index (CI) values were 0.26 (bulk) and 0.30 (CD34+CD38-) for ED50 and 0.93 (bulk) and 0.46 (CD34+CD38-) for ED75, indicating highly synergistic (CI < 1) efficacy in apoptosis induction. The relation between p53 status and sensitivity to Nutlin-induced apoptosis has been well established. Nutlin-resistant samples were much less sensitive to KPT-185 than Nutlin-sensitive cases (12.2 ± 0.06 % versus 30.9 ± 0.04 % Annexin V, P < 0.05). Synergistic induction of apoptosis was not observed in normal cord blood CD34+CD38- cells. Collectively, CRM1 inhibition offers a novel therapeutic strategy for AML that mostly retains wild-type p53. We propose to develop novel combinatorial approaches for the therapy of AML, aimed at maximal activation of p53 and apoptosis signaling by concomitant MDM2 and CRM1 inhibition. Disclosures: Shacham: Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment. Andreeff:Hoffmann-La Roche: Research Funding; Karyopharm Therapeutics: Unrestricted gift, Unrestricted gift Other.

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Janerin Induces Cell Cycle Arrest at the G2/M Phase and Promotes Apoptosis Involving the MAPK Pathway in THP-1, Leukemic Cell Line

Molecules ◽

10.3390/molecules26247555 ◽

2021 ◽

Vol 26 (24) ◽

pp. 7555

Author(s):

Mohammad Z. Ahmed ◽

Fahd A. Nasr ◽

Wajhul Qamar ◽

Omar M. Noman ◽

Javed Masood Khan ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Mapk Pathway ◽

Leukemic Cell ◽

Leukemic Cells ◽

Dependent Manner ◽

Cycle Arrest ◽

M Phase ◽

Human Leukemic Cells ◽

Dose Dependent

Janerin is a cytotoxic sesquiterpene lactone that has been isolated and characterized from different species of the Centaurea genus. In this study, janerin was isolated form Centaurothamnus maximus, and its cytotoxic molecular mechanism was studied in THP-1 human leukemic cells. Janerin inhibited the proliferation of THP-1 cells in a dose-dependent manner. Janerin caused the cell cycle arrest at the G2/M phase by decreasing the CDK1/Cyclin-B complex. Subsequently, we found that janerin promoted THP-1 cell death through apoptosis as indicated by flow cytometry. Moreover, apoptosis induction was confirmed by the upregulation of Bax, cleaved PARP-1, and cleaved caspase 3 and the downregulation of an anti-apoptotic Bcl-2 biomarker. In addition, immunoblotting indicated a dose dependent upregulation of P38-MAPK and ERK1/2 phosphorylation during janerin treatment. In conclusion, we have demonstrated for the first time that janerin may be capable of inducing cell cycle arrest and apoptosis through the MAPK pathway, which would be one of the mechanisms underlying its anticancer activity. As a result, janerin has the potential to be used as a therapeutic agent for leukemia.

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First-in-Class ROR1 Small Molecule Inhibitor (KAN0439834) Downregulated Wnt-Canonical and Non-Canonical Signaling Pathways and Induced Apoptosis of CLL Cells

Blood ◽

10.1182/blood.v126.23.2912.2912 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2912-2912 ◽

Cited By ~ 1

Author(s):

Mohammad Hojjat-Farsangi ◽

Ali Moshfegh ◽

Amir Hossein Daneshmanesh ◽

Jan Vågberg ◽

Byström Styrbjörn ◽

...

Keyword(s):

Tyrosine Kinase ◽

Signaling Pathways ◽

Small Molecule ◽

Intracellular Signaling ◽

Leukemic Cells ◽

Drug Candidate ◽

Dependent Manner ◽

Induced Apoptosis ◽

Dose Dependent

Abstract Background: The receptor tyrosine kinase (RTK) ROR1 is detected during embryogenesis but downregulated in adult normal tissues. However, it is expressed in several solid tumors and hematological malignancies. Targeting ROR1 with specific siRNAs in chronic lymphocytic leukemia (CLL) induced apoptosis of the leukemic cells. Moreover, ROR1 specific monoclonal antibodies (mAbs) dephosphorylated ROR1 followed by apoptosis of the CLL cells. Furthermore, ROR1 tyrosine kinase inhibitors (ROR1-TKI) (small molecule inhibitors) have been shown to dephosphorylate ROR1, downregulate the activated PI3K/AKT/mTOR signaling pathway and induce specific apoptosis of CLL cells. Aim: In the present report we analysed the effects of a ROR1-TKI drug candidate (KAN0439834) on other intracellular signaling pathways involved in cell survival, differentiation and migration in addition to the PI3K/AKT/mTOR pathway in CLL cells. Methods: KAN0439834 ROR1-TKI was derived from a high-throughput screening (HTS) and a chemical synthesis program, including cellular assays for CLL specific cytotoxicity. The compound was also tested for ADME and in vivo pharmacokinetics characteristics. Peripheral blood mononuclear cells (PBMC) were derived from patients with CLL and normal healthy donors. Intracellular signaling molecules were analysed by Western blot (WB) after 30 min incubation of the cells with the ROR1-TKI (50-1000 nM). Apoptosis/necrosis was determined by the MTT cytotoxicity assay and Annexin V/PI staining in flowcytometry after 24 h of incubation. Results: CLL cells expressed ROR1 as determined by WB and flowcytometry. ROR1 was shown to be phosphorylated using a polyclonal anti-phospho-ROR1 (pROR1) antibody (WB). After 30 min of incubation with 50-1000 nM of KAN0439834, ROR1 was dephosphorylated in a dose-dependent manner. KAN0439834 also dephosphorylated LRP6, GSK3β, JNK, MAPK/ERK/p42,44, PKC, Src, and c-Jun and decreased the β-catenin concentration as well as deactivated BCL-2 and Bax proteins. KAN0439834 had no effect on Bruton tyrosine kinase (Btk) phosphorylation involved in B-cell receptor (BCR) signaling. Incubation of CLL cells with KAN0439834 (50-1000 nM) showed a dose dependent induction of apoptosis/necrosis of leukemic cells with more than 80% specific killing of CLL cells after 24 h and an IC50 value of 250 nM. Conclusions: Our data show that KAN0439834 downregulated the activity of various signaling pathways in CLL cells suggested to be connected with ROR1 signaling, including the Wnt-canonical associated molecule as LRP6, GSK3β and β-catenin as well as several Wnt non-canonical associated proteins as Src, MAPK/ERK p42,44, JNK, and PKC and inactivation of c-Jun that was followed by apoptosis of the CLL cells in a dose dependent manner. Further studies are ongoing to study the effects of the ROR1 specific TKIs on ROR1 downstream signaling as well as in preclinical in vivo animal models using human fresh tumors and cell lines to evaluate the anti-tumor effects. Available data suggest a specific ROR1-mediated cytotoxic effect of KAN0439834 on CLL cells, which represents a first-in-class of a novel CLL drug candidate targeting ROR1. Disclosures Moshfegh: Kancera AB: Employment. Vågberg:Kancera AB: Employment. Styrbjörn:Kancera AB: Employment. Schultz:Kancera AB: Employment. Olsson:Kancera AB: Employment. Löfberg:Kancera AB: Employment. Norström:Kancera AB: Employment. Norin:Kancera AB: Employment. Olin:Kancera AB: Employment, Equity Ownership. Österborg:Janssen Cilag: Research Funding.

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Synthesis and Assessment of Novel Anti-chlamydial Benzylidene Acylhydrazides Derivatives

Letters in Drug Design & Discovery ◽

10.2174/1570180814666170526170227 ◽

2018 ◽

Vol 15 (1) ◽

pp. 31-36 ◽

Cited By ~ 5

Author(s):

Xiaofeng Bao ◽

Ying Xue ◽

Chao Xia ◽

Yin Lu ◽

Ningjing Yang ◽

...

Keyword(s):

Inhibitory Effect ◽

Dependent Manner ◽

Iron Starvation ◽

Hydrochloride Salt ◽

Obligate Intracellular ◽

Biphasic Life Cycle ◽

Ic50 Value ◽

Ic50 Values ◽

Dose Dependent ◽

Better Than

Background: Chlamydiae, characterized by a unique biphasic life cycle, are a group of Gram-negative obligate intracellular bacterial pathogens responsible for diseases in a range of hosts including humans. Benzylidene acylhydrazide CF0001 could inhibit chlamydiae independent of iron starvation and T3SS inhibition. This finding promoted us to design and synthesize more benzylidene acylhydrazides to find novel anti-chlamydial agents. Methods: The carboxylic acids 1a-1d were coupled with Boc-hydrazide inpresence of EDCI and DMAP to obtain the intermediate 2a-2d in 60-62% yields. N-Boc deprotections were performed to obtain hydrazide hydrochloride salt 3a-3d. Nextly, the hydrazides were subjected to condensation with aldehydes to obtain benzylidene acylhydrazides 4a-4g in 30-52% yields in two steps. Results: Compound 4d exhibited best inhibitory effect on the formation and growth of chlamydial inclusions. The IC50 value of compound 4d for infectious progenies was 3.55 µM, better than 7.30 µM of CF0001. Conclusion: To find novel anti-chlamydial agents, we have designed and synthesized benzylidene acylhydrazides 4a-4g. Compounds 4a, 4d, 4g showed inhibitory activity on C. muridarum with the IC50 values from 3.55-12 µM. The 3,5-dibromo-4-hydroxyl substitutes on ring B are critical to keep their anti-chlamydial activity. Compound 4d inhibited C. muridarum in a dose-dependent manner without apparent cytotoxicity.

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Targeting BMI-1 with PLGA–PEG nanoparticle-containing PTC209 modulates the behavior of human glioblastoma stem cells and cancer cells

Cancer Nanotechnology ◽

10.1186/s12645-021-00078-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Elham Poonaki ◽

Fatemeh Ariakia ◽

Mohammad Jalili-Nik ◽

Mehdi Shafiee Ardestani ◽

Gholamhossein Tondro ◽

...

Keyword(s):

Drug Loading ◽

Polycomb Group ◽

Dependent Manner ◽

Migration Ability ◽

Jnk Signaling ◽

Human Glioblastoma ◽

Core Member ◽

Ic50 Values ◽

Human Gbm ◽

Dose Dependent

AbstractDespite advances in glioblastoma (GBM) treatments, current approaches have failed to improve the overall survival of patients. The oncogene BMI-1, a core member of the polycomb group proteins, is a potential novel therapeutic target for GBM. To enhance the efficacy and reduce the toxicity, PTC209, a BMI-1 inhibitor, was loaded into a PLGA–PEG nanoparticle conjugated with CD133 antibody (Nano-PTC209) and its effect on the behavior of human GBM stem-like cells (GSCs) and the human glioblastoma cell line (U87MG) was assessed. Nano-PTC209 has a diameter of ~ 75 nm with efficient drug loading and controlled release. The IC50 values of Nano-PTC209 for GSCs and U87MG cells were considerably lower than PTC209. Nano-PTC209 significantly decreased the viability of both GSCs and U87MG cells in a dose-dependent manner and caused a significant enhancement of apoptosis and p53 levels as well as inhibition of AKT and JNK signaling pathways. Furthermore, Nano-PTC209 significantly inhibited the migration ability, decreased the activity of metalloproteinase-2 and -9, and increased the generation of reactive oxygen species in both GSCs and U87MG cells. Our data indicate that PLGA–PEG nanoparticle conjugated with CD133 antibody could be an ideal nanocarrier to deliver PTC209 and effectively target BMI-1 for potential approaches in the treatment of GBM.

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Nonylphenol Induces Apoptosis through ROS/JNK Signaling in a Spermatogonia Cell Line

International Journal of Molecular Sciences ◽

10.3390/ijms22010307 ◽

2020 ◽

Vol 22 (1) ◽

pp. 307

Author(s):

Hyun-Jung Park ◽

Ran Lee ◽

Hyunjin Yoo ◽

Kwonho Hong ◽

Hyuk Song

Keyword(s):

Molecular Mechanisms ◽

Mapk Signaling ◽

Ros Generation ◽

Dependent Manner ◽

Jnk Signaling ◽

Apoptosis Markers ◽

Testicular Size ◽

Spermatogonia Cell ◽

Induced Apoptosis ◽

Dose Dependent

Nonylphenol (NP) is an endocrine-disruptor chemical that negatively affects reproductive health. Testes exposure to NP results in testicular structure disruption and a reduction in testicular size and testosterone levels. However, the effects of NP on spermatogonia in testes have not been fully elucidated. In this study, the molecular mechanisms of NP in GC-1 spermatogonia (spg) cells were investigated. We found that cell viability significantly decreased and apoptosis increased in a dose-dependent manner when GC-1 spg cells were exposed to NP. Furthermore, the expression levels of the pro-apoptotic proteins increased, whereas anti-apoptosis markers decreased in NP-exposed GC-1 spg cells. We also found that NP increased reactive oxygen species (ROS) generation, suggesting that ROS-induced activation of the MAPK signaling pathway is the molecular mechanism of NP-induced apoptosis in GC-1 spg cells. Thus, NP could induce c-Jun phosphorylation; dose-dependent expression of JNK, MKK4, p53, and p38; and the subsequent inhibition of ERK1/2 and MEK1/2 phosphorylation. The genes involved in apoptosis and JNK signaling were also upregulated in GC-1 spg cells treated with NP compared to those in the controls. Our findings suggest that NP induces apoptosis through ROS/JNK signaling in GC-1 spg cells.

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Cytotoxic Effects of Ferula Latisecta on Human Glioma U87 Cells

Drug Research ◽

10.1055/a-0986-6543 ◽

2019 ◽

Vol 69 (12) ◽

pp. 665-670 ◽

Cited By ~ 6

Author(s):

Mohammad Jalili-Nik ◽

Hamed Sabri ◽

Ehsan Zamiri ◽

Mohammad Soukhtanloo ◽

Mostafa Karimi Roshan ◽

...

Keyword(s):

Enzymatic Activity ◽

Gelatin Zymography ◽

Annexin V ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Ic50 Values ◽

Induced Apoptosis ◽

Natural Herb ◽

First Time ◽

U87 Cells

AbstractGlioblastoma multiforme (GBM) is the fatal type of astrocytic tumors with a survival rate of 12 months. The present study, for the first time, evaluated the cytotoxic impacts of Ferula latisecta (F. latisecta) hydroalcoholic extract on U87 GBM cell line. The MTT assay measured the cellular toxicity following 24- and 48 h treatment with various doses of F. latisecta (0–800 μg/mL). Apoptosis was evaluated by an Annexin V/propidium iodide (PI) staining 24 h after treatment by F. latisecta. Moreover, to determine the cellular metastasis of U87 cells, we used a gelatin zymography assay (matrix metalloproteinase [MMP]-2/-9 enzymatic activity). The outcomes showed that F. latisecta mitigated the viability of U87 cells in a concentration- and time-dependent manner with IC50 values of 145.3 and 192.3 μg/mL obtained for 24- and 48 h treatments, respectively. F. latisecta induced apoptosis in a concentration-dependent manner after 24 h. Also, MMP-9 activity was significantly decreased following 24 h after treatment concentration-dependently with no change in MMP-2 enzymatic activity. This study showed that F. latisecta induced cytotoxicity and apoptosis, and mitigated metastasis of U87 GBM cells. Hence, F. latisecta could be beneficial as a promising natural herb against GBM after further studies.

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Synthesis and In Vitro Antitumor Activity of Novel Bivalent β-Carboline-3-carboxylic Acid Derivatives with DNA as a Potential Target

International Journal of Molecular Sciences ◽

10.3390/ijms19103179 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3179 ◽

Cited By ~ 4

Author(s):

Hongling Gu ◽

Na Li ◽

Jiangkun Dai ◽

Yaxi Xi ◽

Shijun Wang ◽

...

Keyword(s):

Antitumor Activity ◽

Cell Apoptosis ◽

Docking Studies ◽

In Vitro Cytotoxicity ◽

Dependent Manner ◽

Cycle Arrest ◽

Dna Binding Affinity ◽

Dose Dependent ◽

Mcf 7

A series of novel bivalent β-carboline derivatives were designed and synthesized, and in vitro cytotoxicity, cell apoptosis, and DNA-binding affinity were evaluated. The cytotoxic results demonstrated that most bivalent β-carboline derivatives exhibited stronger cytotoxicity than the corresponding monomer against the five selected tumor cell lines (A549, SGC-7901, Hela, SMMC-7721, and MCF-7), indicating that the dimerization at the C3 position could enhance the antitumor activity of β-carbolines. Among the derivatives tested, 4B, 6i, 4D, and 6u displayed considerable cytotoxicity against A549 cell line. Furthermore, 4B, 6i, 4D, and 6u induced cell apoptosis in a dose-dependent manner, and caused cell cycle arrest at the S and G2/M phases. Moreover, the levels of cytochrome C in mitochondria, and the expressions of bcl-2 protein, decreased after treatment with β-carbolines, which indicated that 6i and 6u could induce mitochondria-mediated apoptosis. In addition, the results of UV-visible spectral, thermal denaturation, and molecular docking studies revealed that 4B, 6i, 4D, and 6u could bind to DNA mainly by intercalation.

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