scholarly journals Modulated Electro-Hyperthermia Supports the Effect of Gemcitabine Both in Sensitive and Resistant Pancreas Adenocarcinoma Cell Lines

2021 ◽  
Vol 27 ◽  
Author(s):  
Gertrud Forika ◽  
Eva Kiss ◽  
Gabor Petovari ◽  
Titanilla Danko ◽  
Aron Bertram Gellert ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Kinase Inhibitor ◽  
Treatment Resistance ◽  
Inhibitory Effect ◽  
Ductal Adenocarcinoma ◽  
Phase Cell ◽  
M Phase ◽  
Elevated Expression ◽  
Cell Cycle Inhibition

The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is frequently associated to high treatment resistance. Gemcitabine (GEM) alone or in combination is the most used chemotherapy for unresecable PDACs. Here we studied whether modulated electro-hyperthermia (mEHT), a non-invasive complementary treatment, can support the effect of GEM on PDAC cells in vitro. The LD20 for the GEM-resistant Panc1 cells proved to be 200× higher than for the drug-sensitive Capan1. The mEHT alone caused significant apoptosis in Capan1 cultures as confirmed by the elevated SubG1 phase cell fraction and increased number of cleaved Caspase-3 positive cells 48 h after treatment, with an additive effect when GEM was used after hyperthermia. These were accompanied by reduced number of G1, S, and G2/M phase cells and elevated expression of the cyclin-dependent kinase inhibitor p21waf1 protein. In GEM-resistant Panc1 cells, an initial apoptosis was detected by flow cytometry 24 h after mEHT ± GEM treatment, which however diminished by 48 h at persistent number of cleaved Caspase-3 positive tumor cells. Though GEM monotherapy reduced the number of tumor progenitor colonies in Capan1 cell line, an additive colony inhibitory effect of mEHT was observed after mEHT + GEM treatment. The heat shock induced Hsp27 and Hsp70 proteins, which are known to sensitize PDAC cells to GEM were upregulated in both Capan1 and Panc1 cells 24 h after mEHT treatment. The level of E-Cadherin, a cell adhesion molecule, increased in Capan1 cells after mEHT + GEM treatment. In conclusion, in GEM-sensitive PDAC cells mEHT treatment alone induced cell death and cell cycle inhibition and improved GEM efficiency in combination, which effects were milder and short-term up to 24 h in the GEM-resistant Panc1 cells. Our data further support the inclusion of hyperthermia, in particular of mEHT, into the traditional oncotherapy regimens of PDAC.

Novel Thiadiazoline Spiro Quinoline Analogues Induced Cell death in MCF-7 cells via G2/M Phase Cell Cycle Arrest

2021 ◽  
Author(s):  
Selvaraj Shyamsivappan ◽  
Raju Vivek ◽  
Thangaraj Suresh ◽  
Adhigaman Kaviyarasu ◽  
Sundarasamy Amsaveni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Spectroscopic Studies ◽  
Phase Cell ◽  
Quinoline Derivatives ◽  
Cycle Arrest ◽  
M Phase ◽  
Mcf 7

Abstract A progression of novel thiadiazoline spiro quinoline derivatives were synthesized from potent thiadiazoline spiro quinoline derivatives . The synthesized compounds portrayed by different spectroscopic studies and single X-ray crystallographic studies. The compounds were assessed for in vitro anticancer properties towards MCF-7 and HeLa cells. The compounds showed superior inhibition action MCF-7 malignant growth cells. Amongst, the compound 4a showed significant inhibition activity, the cell death mechanism was evaluated by fluorescent staining, and flow cytometry, RT-PCR, and western blot analyses. The in vitro anticancer results revealed that the compound 4a induced apoptosis by inhibition of estrogen receptor alpha (ERα) and G2/M phase cell cycle arrest. The binding affinity of the compounds with ERα and pharmacokinetic properties were confirmed by molecular docking studies.

Beauvericin Inhibits the Growth of U251 Glioma Cells and Promotes Apoptosis In Vitro

2020 ◽  
Vol 14 (5) ◽  
pp. 639-644
Author(s):  
Liming Hu ◽  
Tianyi Zhao ◽  
Jia Wang ◽  
Renguang Wang ◽  
Hongshi Bu ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Glioma Cells ◽  
Inhibitory Effect ◽  
U251 Cell ◽  
Western Blot Assay ◽  
Expression Levels ◽  
Signal Transduction Proteins

To elucidated the inhibitory effect of beauvericin (BEA) on glioma cells and its possible molecular mechanism, in this study, the MTT assay was performed to observed the effect of BEA on cell proliferation, the flow cytometry was used to measure its protective effect on cell apoptosis, and the Western Blot assay was performed to test the expression levels of signal transduction proteins. In the results, the concentration of BEA was 0.5 μmoL/L in the drug group, indicating that it has obvious protect effect to the U251 cells. The apoptosis rates of BEA, Cis and BEA+Cis groups, compared with the U251 group, were 2.93, 3.71 and 5.0 times higher respectively. In addition, the expression levels of Cyclin D1, E, B and Bcl-2 in BEA group were 75, 69, 78 and 67% of that in the U251 group, while Bax and cleaved caspase-3 were twice as much as that in the U251 group. In conclusion, beauvericin can inhibit U251 cell apoptosis and the possible mechanism is to reduce the expression of Cyclin D1, B, E and Bcl-2, while the levels of Bax and cleaved Caspase-3 increased. Thus, BEA has a broad application prospect in the treatment of glioma.

scholarly journals Carbohydrate 3′-sialyllactose as a novel target for theranostics in pancreatic ductal adenocarcinoma

Tumor Biology ◽  
2020 ◽  
Vol 42 (10) ◽  
pp. 101042832096527
Author(s):  
Kiyoshi Higashi ◽  
Keiko Maeda ◽  
Kaori Miyata ◽  
Saori Yoshimura ◽  
Keita Yamada ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Ductal Adenocarcinoma ◽  
Significant Activity ◽  
Gastric Cancer Cells ◽  
Complement Dependent Cytotoxicity ◽  
Elevated Expression ◽  
Novel Target

We previously demonstrated that the carbohydrate 3′-sialyllactose is overexpressed in cancer stem-like cells such as metastatic pancreatic and poorly differentiated gastric cancer cells, and undifferentiated human embryonic stem cells. In this study, we investigated the possibility of 3′-sialyllactose as a target for theranostics in cancers using a recombinant mouse monoclonal antibody r3B1E2 that binds to 3′-sialyllactose. Immunohistochemistry analysis confirmed an elevated expression of 3′-sialyllactose in tumors of pancreas, stomach, and testis, while no expression of 3′-sialyllactose was observed in corresponding normal controls. In addition, a stage-independent expression of 3′-sialyllactose was observed, especially in pancreatic ductal adenocarcinoma (PDAC). The level of serum 3′-sialyllactose in PDAC subjects was significantly higher than that in healthy controls, providing excellent AUC of 0.88. We next explored the therapeutic potential of r3B1E2 for PDAC in vitro. Treatment of r3B1E2 with 3′-sialyllactose-bearing human PDAC cells exhibited a complement-dependent cytotoxicity, whereas no significant activity of r3B1E2 against 3′-sialyllactose-negative cells was observed. Collectively, these findings raise the possibility of 3′-sialyllactose as a novel target for theranostics in PDAC.

scholarly journals (S)-10-Hydroxycamptothecin Inhibits Esophageal Squamous Cell Carcinoma Growth In Vitro and In Vivo Via Decreasing Topoisomerase I Enzyme Activity

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1964 ◽  
Author(s):  
Mengqiu Song ◽  
Shuying Yin ◽  
Ran Zhao ◽  
Kangdong Liu ◽  
Joydeb Kumar Kundu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Enzymatic Activity ◽  
Topoisomerase I ◽  
Cell Cycle Progression ◽  
Caspase 3 ◽  
Cyclin B1 ◽  
Phase Cell ◽  
Cycle Progression

Topoisomerase (TOP) I plays a major role in the process of supercoiled DNA relaxation, thereby facilitating DNA replication and cell cycle progression. The expression and enzymatic activity of TOP I is positively correlated with tumor progression. Although the anticancer activity of (S)-10-Hydroxycamptothecin (HCPT), a TOP I specific inhibitor, has been reported in various cancers, the effect of HCPT on esophageal cancer is yet to be examined. In this study, we investigate the potential of HCPT to inhibit the growth of ESCC cells in vitro and verify its anti-tumor activity in vivo by using a patient-derived xenograft (PDX) tumor model in mice. Our study revealed the overexpression of TOP I in ESCC cells and treatment with HCPT inhibited TOP I enzymatic activity at 24 h and decreased expression at 48 h and 72 h. HCPT also induced DNA damage by increasing the expression of H2A.XS139. HCPT significantly decreased the proliferation and anchorage-independent growth of ESCC cells (KYSE410, KYSE510, KYSE30, and KYSE450). Mechanistically, HCPT inhibited the G2/M phase cell cycle transition, decreased the expression of cyclin B1, and elevated p21 expression. In addition, HCPT stimulated ESCC cells apoptosis, which was associated with elevated expression of cleaved PARP, cleaved caspase-3, cleaved caspase-7, Bax, Bim, and inhibition of Bcl-2 expression. HCPT dramatically suppressed PDX tumor growth and decreased the expression of Ki-67 and TOP I and increased the level of cleaved caspase-3 and H2A.XS139 expression. Taken together, our data suggested that HCPT inhibited ESCC growth, arrested cell cycle progression, and induced apoptosis both in vitro and in vivo via decreasing the expression and activity of TOP I enzyme.

The Novel Aurora Kinase Inhibitor ENMD-2076 Has Potent Single Agent Activity against Multiple Myeloma (MM) in Vitro and in Vivo, and Shows Synergistic Activity in Combination with Lenalidomide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3660-3660 ◽  
Author(s):  
Xiaojing Wang ◽  
Anthony L. Sinn ◽  
Attaya Suvannasankha ◽  
Colin D. Crean ◽  
Li Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Caspase 3 ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Synergistic Activity ◽  
Significant Activity ◽  
Aurora A Kinase ◽  
Free Base

Abstract ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against Aurora A kinase as well as multiple receptor tyrosine kinases (RTK). We investigated the single agent activity of ENMD-2076 against MM cells in vitro and in vivo, and in combination with lenalidomide. ENMD-2076 free base showed significant cytotoxicity against MM cells with a mean LC50 of 3.84±0.86 μM at 48 hours in vitro. Cytotoxicity was associated with cleavage of caspase 3, 8, 9 and PARP, and loss of mitochondrial membrane potential as early as 6 hours. ENMD-2076 free base inhibited c-kit, FGFR-1, 3 and VEGFR1 and subsequently inhibition of downstream targets phosphorylated (p)-BAD, p-Foxo1a and p-GSK-3β was observed at 6 hours. NOD/SCID mice implanted with H929 human plasmacytoma xenografts and treated for 30 days with 50, 100, 200mg/kg/d ENMD-2076 showed a dose-dependent inhibition of tumor growth (Figure 1), with minimal toxicity as assessed by the stable weight of treated animals. Immunohistochemical staining of tumors from sacrificed animals showed significant reduction in Ki67 at all dose levels of treatment compared to control tumors. An increase in cleaved caspase-3 was observed on Western blot from the lysates of H929 tumors obtained from treated animals. ENMD-2076 free base also showed synergistic cytotoxic activity when combined with lenalidomide against H929, MM1.R and MM1.S cells as assessed by MTT assay and Annexin-V/PI staining. Using the Chou-Talalay method, the combination indices (CI) were < 1 for all three cell lines across a range of concentrations of ENMD-2076 free base (0.25–1.0 μM) plus lenalidomide (2.5–10 μM) indicating synergistic activity (CI=0.362 H929; CI=0.315 MM1.R; CI=0.415 MM1.S). Our results provide rationale for the investigation of ENMD-2076 alone and in combination with lenalidomide in patients with multiple myeloma. Figure Figure

scholarly journals Porphyra-334, a mycosporine-like amino acid, attenuates UV-induced apoptosis in HaCaT cells

2017 ◽  
Vol 67 (2) ◽  
pp. 257-264 ◽  
Author(s):  
Sung-Suk Suh ◽  
Se Kyung Oh ◽  
Sung Gu Lee ◽  
Il-Chan Kim ◽  
Sanghee Kim
Keyword(s):  
Caspase 3 ◽  
Biological Activities ◽  
Inhibitory Effect ◽  
In Vitro Assays ◽  
Control Group ◽  
Hacat Cells ◽  
Dramatic Decrease ◽  
Induced Apoptosis ◽  
Active Caspase

Abstract The main aim of the current research was to study the effect of porphyra-334, one of mycosporine-like amino acids (MAAs), well known as UV-absorbing compounds, on UVinduced apoptosis in human immortalized keratinocyte (HaCaT) cells. Due to their UV-screening capacity and ability to prevent UV-induced DNA damage, MAAs have recently attracted considerable attention in both industry and research in pharmacology. Herein, human HaCaT cells were used to determine the biological activities of porphyra- 334 by various in vitro assays, including proliferation, apoptosis and Western blot assays. The proliferation rate of UV-irradiated HaCaT cells was significantly decreased compared to the control group. Pretreatment with porphyra- 334 markedly attenuated the inhibitory effect of UV and induced a dramatic decrease in the apoptotic rate. Expression of active caspase-3 protein was increased in response to UV irradiation, while caspase-3 levels were similar between cells treated with porphyra-334 and the non-irradiated control group. Taken together, our data suggest that porphyra-334 inhibits UV-induced apoptosis in HaCaT cells through attenuation of the caspase pathway.

scholarly journals Effect of Pterostilbene, a Natural Derivative of Resveratrol, in the Treatment of Colorectal Cancer through Top1/Tdp1-Mediated DNA Repair Pathway

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4002
Author(s):  
Yutian Zhang ◽  
Ying Li ◽  
Changcheng Sun ◽  
Xiang Chen ◽  
Luyao Han ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Inhibitory Effect ◽  
Repair Pathway ◽  
Topoisomerase 1 ◽  
Tumor Drug Resistance ◽  
Significant Toxicity ◽  
M Phase ◽  
Natural Derivative ◽  
Transplantation Model

Topoisomerase 1 (Top1) inhibitor is an effective anticancer drug, but several factors limit its clinical application such as drug inactivation, tyrosyl-DNA phosphodiesterase 1 (Tdp1)-mediated tumor drug resistance, and its toxicity. Our previous study identified pterostilbene (PTE) and resveratrol (RE) to suppress these two proteins by binding to their active center. PTE and RE could inhibit the proliferation of various colorectal cancer cells, induce cell apoptosis, and make cell cycle stay in G2/M phase in vitro. PTE and RE could decrease Top1 and Tdp1 contents and mRNA expression in wild-type, constructed Tdp1 overexpressing CL187, Top1- or Tdp1- silenced CL187 cell lines. PTE exhibited excellent antitumor activity in subcutaneous CL187 transplantation model (TGI = 79.14 ± 2.85%, 200 mg/kg, i.p.) and orthotopic transplantation model (TGI = 76.57 ± 6.34%, 100 mg/kg, i.p.; TGI = 72.79 ± 4.06%, 500 mg/kg, i.g.) without significant toxicity. PTE had no significant inhibitory effect on non-tumor cell proliferation in vitro and would not induce damage to liver, kidney, and other major organs. Overall, PTE and RE can inhibit the activity of Top1 enzyme and inhibit the DNA damage repair pathway mediated by Top1/Tdp1, and can effectively inhibit colorectal cancer development with low toxicity, thus they have great potential to be developed into a new generation of anti-tumor drugs.

scholarly journals Romidepsin Induces G2/M Phase Arrest and Apoptosis in Cholangiocarcinoma Cells

2020 ◽  
Vol 19 ◽  
pp. 153303382096075
Author(s):  
Pihong Li ◽  
Luguang Liu ◽  
Xiangguo Dang ◽  
Xingsong Tian
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Antitumor Effect ◽  
Caspase 3 ◽  
M Cell ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
M Phase

Background: Cholangiocarcinoma (CCA) is an extremely intractable malignancy since most patients are already in an advanced stage when firstly discovered. CCA needs more effective treatment, especially for advanced cases. Our study aimed to evaluate the effect of romidepsin on CCA cells in vitro and in vivo and explore the underlying mechanisms. Methods: The antitumor effect was determined by cell viability, cell cycle and apoptosis assays. A CCK-8 assay was performed to measure the cytotoxicity of romidepsin on CCA cells, and flow cytometry was used to evaluate the effects of romidepsin on the cell cycle and apoptosis. Moreover, the in vivo effects of romidepsin were measured in a CCA xenograft model. Results: Romidepsin could reduce the viability of CCA cells and induce G2/M cell cycle arrest and apoptosis, indicating that romidepsin has a significant antitumor effect on CCA cells in vitro. Mechanistically, the antitumor effect of romidepsin on the CCA cell lines was mediated by the induction of G2/M cell cycle arrest and promotion of cell apoptosis. The G2/M phase arrest of the CCA cells was associated with the downregulation of cyclinB and upregulation of the p-cdc2 protein, resulting in cell cycle arrest. The apoptosis of the CCA cells induced by romidepsin was attributed to the activation of caspase-3. Furthermore, romidepsin significantly inhibited the growth of the tumor volume of the CCLP-1 xenograft, indicating that romidepsin significantly inhibited the proliferation of CCA cells in vivo. Conclusions: Romidepsin suppressed the proliferation of CCA cells by inducing cell cycle arrest through cdc2/cyclinB and cell apoptosis by targeting caspase-3/PARP both in vitro and in vivo, indicating that romidepsin is a potential therapeutic agent for CCA.

Lycorine Modulates the Expression of p21 Via a p53-Independent Pathway in HL-60 Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4297-4297
Author(s):  
Jing Liu ◽  
Shu-Ling Wang ◽  
Lin Fang ◽  
Mao Ye ◽  
Zhi-Wei Sun ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Fold Increase ◽  
Alternative Pathways ◽  
Cyclin Dependent Kinase Inhibitor ◽  
M Phase ◽  
Induced Apoptosis

Abstract Abstract 4297 Leukemia is one of the most life-threatening cancers today, and acute promyelogenous leukemia is a common type of leukemia. We have previously shown that lycorine, a natural alkaloid extract from Amaryllidaceae, exhibited anti-leukemia effects in vitro and in vivo. Lycorine treatment of HL-60 cell arrested cell cycle at G2/M phase and induced apoptosis. In the present study, we sought to explore the molecular mechanisms for the anti-leukemia action of lycorine. Gene chip analysis revealed that lycorine treatment of HL-60 cells induced more than 9 fold increase of p21, a cyclin-dependent kinase inhibitor, whose expression is mainly regulated by p53. Since HL-60 cells are p53 null, the above findings suggest that lycorine activates p21 expression through p53-independent pathway. To further explore the alternative pathways for the activation of p21 induced by lycorine, we examined the effect of lycorine on the expression of Rb, pRb, E2F, c-Myc and HDACs which have shown to regulate p21 expression. We show that expression of pRb (ser780) and c-Myc was down-regulated, Rb and E2F were up-regulated, while the expression of HDAC1 and HDAC3 was not changed. Together these findings suggest that lycorine exerts its anti-leukemia effect by activating p21 expression via pRb/E2F and c-Myc pathways. Disclosures: No relevant conflicts of interest to declare.

Effect of dehydroleucodine on meiosis reinitiation in Bufo arenarum denuded oocytes

Zygote ◽  
2007 ◽  
Vol 15 (2) ◽  
pp. 183-187 ◽  
Author(s):  
G. Sánchez Toranzo ◽  
O.S. Giordano ◽  
L.A. López ◽  
M.I. Bühler
Keyword(s):  
Germinal Vesicle ◽  
Inhibitory Effect ◽  
Follicle Cells ◽  
Dependent Manner ◽  
Bufo Arenarum ◽  
M Phase ◽  
Amplification Loop ◽  
Activation Cascade ◽  
P34 Cdc2

SummaryIn amphibian oocytes meiosis, the transition from G2 to M phase is regulated by the maturation promoting factor (MPF), a complex of the cyclin-dependent kinase p34/cdc2 and cyclin B. In immature oocytes there is an inactive complex (pre-MPF), in which cdc2 is phosphorylated on both Thr-161 and Thr-14/Tyr-15 residues. The dephosphorylation of Thr-14/Tyr-15 is necessary for the start of MPF activation and it is induced by the activation of cdc25 phosphatase. Late, to complete the activation, a small amount of active MPF induces an auto-amplification loop of MPF stimulation (MPF amplification). Dehydroleucodine (DhL) is a sesquiterpenic lactone that inhibits mammalian cell proliferation in G2. We asked whether DhL interferes with MPF activation. For this question, the effect of DhL (up to 30 μM) on the resumption of meiosis was evaluated, and visualized by germinal vesicle break down (GVBD), of Bufo arenarum oocytes induced in vitro by either: (i) removing follicle cells; (ii) progesterone stimulation; (iii) VG-content injection; or (iv) injection of mature cytoplasm. The results show that DhL induced GVBD inhibition, in a dose-dependent manner, in spontaneous and progesterone-induced oocyte maturation. Nevertheless, DhL at the doses assayed had no effect on GVBD induced by mature cytoplasm injection, but exerted an inhibitory effect on GVBD induced by GV content. On the basis of these results, we interpreted that DhL does not inhibit MPF amplification and that the target of DhL is any event in the early stages of the cdc25 activation cascade.

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