scholarly journals Design and Synthesis of Novel Betulin Derivatives Containing Thio-/Semicarbazone Moieties as Apoptotic Inducers through Mitochindria-Related Pathways

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6356
Author(s):  
Jiafeng Wang ◽  
Jiale Wu ◽  
Yinglong Han ◽  
Jie Zhang ◽  
Yu Lin ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Antitumor Agents ◽  
Carcinoma Cells ◽  
Caspase 9 ◽  
Apoptosis Pathway ◽  
Design And Synthesis ◽  
Lung Carcinoma Cells ◽  
Betulin Derivatives ◽  
Mcf 7

Two new series of betulin derivatives with semicarbazone (7a–g) or thiosemicarbazone (8a–g) groups at the C-28 position were synthesized. All compounds were evaluated for their in vitro cytotoxicities in human hepatocellular carcinoma cells (HepG2), human breast carcinoma cells (MCF-7), human lung carcinoma cells (A549), human colorectal cells (HCT-116) and normal human gastric epithelial cells (GES-1). Among these compounds, 8f displayed the most potent cytotoxicity with an IC50 value of 5.86 ± 0.61 μM against MCF-7 cells. Furthermore, the preliminary mechanism studies in MCF-7 cells showed that compound 8f could trigger the intracellular mitochondrial-mediated apoptosis pathway by losing MMP level, which was related with the upregulation of Bax, P53 and cytochrome c expression; the downregulation of Bcl-2 expression; activation of the expression levels of caspase-3, caspase-9, cleaved caspase-3 and cleaved caspase-9; and an increase in the amounts of intracellular reactive oxygen species. These results indicated that compound 8f may be used as a valuable skeleton structure for developing novel antitumor agents.

scholarly journals A novel Bcl-2 inhibitor, BM-1197, Induces apoptosis in Malignant Lymphoma Cells through the Endogenous Apoptotic Pathway

2019 ◽  
Author(s):  
Yue-Li Sun ◽  
Wen-Qi Jiang ◽  
Qiu-Yun Luo ◽  
Da-Jun Yang ◽  
Yu-Chen Cai ◽  
...  
Keyword(s):  
Malignant Lymphoma ◽  
Caspase 3 ◽  
Caspase 9 ◽  
Antitumor Effects ◽  
Lymphoma Cells ◽  
Dual Inhibitor ◽  
Apoptosis Pathway ◽  
Xenograft Models

Abstract Background: Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family protein can be new strategy for malignant lymphoma treatment. In this study, we investigate the antitumor effect and the cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor BM-1197 in DCBCL and Burkitt lymphoma cells. Methods: CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using the caspase-3/ caspase-9 activity kit. Western blotting analysis was performed to evaluate the change of protein expression. The functional analysis was evalueated via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. Results: We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells which harbor Bcl-2 and Bcl-xL high expression in vitro and has synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interaction of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, PUMA/Bcl-2 and induced conformational change in the Bax protein.which results in activation of Bax and release cytochrome c, and activated caspase -9, -3, -7 and finally induce cell apoptosis. Furthermore, our data demonstrates that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. Conclusions: Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo, and provides promising preclinical data for further development of BM-1197 in malignant lymphoma.

scholarly journals A novel Bcl-2 inhibitor, BM-1197, induces apoptosis in malignant lymphoma cells through the endogenous apoptotic pathway

BMC Cancer ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Yue-Li Sun ◽  
Wen-Qi Jiang ◽  
Qiu-Yun Luo ◽  
Da-Jun Yang ◽  
Yu-Chen Cai ◽  
...  
Keyword(s):  
Malignant Lymphoma ◽  
Caspase 3 ◽  
Caspase 9 ◽  
Antitumor Effects ◽  
Lymphoma Cells ◽  
Dual Inhibitor ◽  
Apoptosis Pathway ◽  
Xenograft Models

Abstract Background Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family proteins may be a new strategy for the treatment of malignant lymphoma. In this study, we investigate the antitumor effect and cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor, BM-1197, in DCBCL and Burkitt lymphoma cells. Methods The CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using a caspase-3/caspase-9 activity kit. Western blotting analysis was performed to evaluate the changes in protein expression. Functional analysis was performed via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. Results We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells that harbor high expression of Bcl-2 and Bcl-xL in vitro and has a synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interactions of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, and PUMA/Bcl-2 and induces conformational changes in the Bax protein, which result in the activation of Bax and release of cytochrome c, activate caspase − 9, − 3, and − 7 and finally induce cell apoptosis. Furthermore, our data demonstrate that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. Conclusions Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo and provides promising preclinical data for the further development of BM-1197 in malignant lymphoma.

scholarly journals A novel Bcl-2 inhibitor, BM-1197, Induces apoptosis in Malignant Lymphoma Cells through the Endogenous Apoptotic Pathway

2019 ◽  
Author(s):  
Yue-Li Sun ◽  
Wen-Qi Jiang ◽  
Qiu-Yun Luo ◽  
Da-Jun Yang ◽  
Yu-Chen Cai ◽  
...  
Keyword(s):  
Malignant Lymphoma ◽  
Caspase 3 ◽  
Caspase 9 ◽  
Antitumor Effects ◽  
Lymphoma Cells ◽  
Dual Inhibitor ◽  
Apoptosis Pathway ◽  
Xenograft Models

Abstract Background: Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family protein can be new strategy for malignant lymphoma treatment. In this study, we investigate the antitumor effect and the cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor BM-1197 in DCBCL and Burkitt lymphoma cells. Methods: CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using the caspase-3/ caspase-9 activity kit. Western blotting analysis was performed to evaluate the change of protein expression. The functional analysis was evalueated via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. Results: We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells which harbor Bcl-2 and Bcl-xL high expression in vitro and has synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interaction of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, PUMA/Bcl-2 and induced conformational change in the Bax protein.which results in activation of Bax and release cytochrome c, and activated caspase -9, -3, -7 and finally induce cell apoptosis. Furthermore, our data demonstrates that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. Conclusions: Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo, and provides promising preclinical data for further development of BM-1197 in malignant lymphoma.

scholarly journals Tiazofurin inhibits oral cancer growth in vitro and in vivo via upregulation of miR-204 expression

2020 ◽  
Vol 19 (7) ◽  
pp. 1377-1382
Author(s):  
Xiaoying Tang ◽  
Aimin Zhao ◽  
Yanhuan Hong
Keyword(s):  
Oral Cancer ◽  
Cancer Cells ◽  
Caspase 3 ◽  
Carcinoma Cells ◽  
Cancer Growth ◽  
Caspase 9 ◽  
Diphenyltetrazolium Bromide ◽  
Oral Cancer Cells

Purpose: To investigate the effect of tiazofurin on proliferation and growth of oral cancer cells, and the associated mechanism(s) of action.Methods: The effect of tiazofurin on the cytotoxicity of SCC-VII and SCC-25 oral cancer cells were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while cell apoptosis was determined by flow cytometry. Western blotting was used for assaying proteinexpressions.Results: Tiazofurin inhibited the viability of the oral cancer cells in a concentration-based manner (p < 0.05). Tiazofurin treatment at a dose of 2.0 μM reduced the proliferation of SCC-VII and SCC-25 cells to 25 and 22 %, respectively. Apoptosis was significantly increased in SCC-VII and SCC-25 cells by tiazofurin treatment, relative to untreated cells (p < 0 .05). Tiazofurin also increased the activation levels of caspase-3 and caspase-9 and downregulated the expressions of p-Akt and p-mTOR in the two cancer cell lines. Moreover, miR-204 expression was significantly promoted in the tiazofurin-treated cells, when compared to control (p < 0 .05). In SCC-VII cells, treatment with tiazofurin suppressed Factin expression, relative to control.Conclusion: These results demonstrate that tiazofurin inhibits the viability and proliferation of SCC-VII and SCC-25 cancer cells via induction of apoptosis and activation of caspase-3/caspase-9. Moreover, tiazofurin targets Akt/mTOR pathway, and upregulats the expressions of F-actin and miR-204 in the oral carcinoma cells. These findings suggest that tiazofurin has a potential for use as an effective treatment for oral cancer. Keywords: Oral cancer, Tiazofurin, Apoptosis, Caspase, Cytotoxicity

109. TROPHOBLAST DEPORTATION IS DEPENDENT UPON CASPASES 3, 8 AND ROCK

2009 ◽  
Vol 21 (9) ◽  
pp. 28
Author(s):  
K. J. Askelund ◽  
P. Stone ◽  
L. W. Chamley
Keyword(s):  
Caspase 3 ◽  
First Trimester ◽  
Normal Pregnancy ◽  
Maternal Blood ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Apoptotic Pathway ◽  
Apoptosis Pathway ◽  
Villous Trophoblast

Background: Trophoblast deportation is the process whereby multinucleated fragments of the syncytiotrophoblast are shed from the placenta into the maternal blood. It is estimated that 150,000 are shed from the placenta and deported daily in normal pregnancy and that more are shed during preeclampsia1. In normal pregnancy deported trophoblasts are thought to die by apoptosis, which is also increased in villous trophoblast in preeclampsia2. However, experimental confirmation that apoptosis leads to trophoblast shedding is required and it is not clear which components of the apoptotic pathway are involved in trophoblast shedding. Objectives: To determine the effect of inhibiting caspase 3 (executioner), caspases 8 and 9 (initiators), and Rho-associated kinase (ROCK; bleb formation) on the number of trophoblasts shed from first trimester human placentae. Methods : Using an in vitro placental explant model of trophoblast deportation, first trimester placentae were cultured for 72 hours in media containing specific inhibitors of ROCK, caspases 3, 8 or 9. Trophoblasts shed from quintuple explants/inhibitor from five placentae were depleted of contaminating leucocytes and erythrocytes, labelled with trypan blue and the sizes and numbers of shed trophoblasts quantified using a Nexcelom automated counter. Results: The number of trophoblasts that were shed from the explants was significantly increased (p=0.04) when caspase 3 (2.4 fold) and caspase 8 (2.7 fold) were inhibited. There was no significant change following caspase 9 inhibition. The number of shed trophoblasts was significantly decreased when ROCK was inhibited. None of the inhibitors significantly altered the size of the shed trophoblasts. Conclusion: Our data suggest that the apoptosis pathway is involved in trophoblast shedding in vitro from first trimester placentae. That caspase 8 but not caspase 9 affected shedding suggests trophoblasts from normal placentae are induced to die via the extrinsic apoptosis pathway. Aberrant regulation of the apoptosis pathway may contribute to pregnancy pathology.

scholarly journals A novel Bcl-2 inhibitor, BM-1197, Induces apoptosis in Malignant Lymphoma Cells through the Endogenous Apoptotic Pathway

2019 ◽  
Author(s):  
Yue-Li Sun ◽  
Wen-Qi Jiang ◽  
Qiu-Yun Luo ◽  
Da-Jun Yang ◽  
Yu-Chen Cai ◽  
...  
Keyword(s):  
Malignant Lymphoma ◽  
Caspase 3 ◽  
Caspase 9 ◽  
Antitumor Effects ◽  
Lymphoma Cells ◽  
Dual Inhibitor ◽  
Apoptosis Pathway ◽  
Xenograft Models

Abstract Background: Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family protein can be new strategy for malignant lymphoma treatment. In this study, we investigate the antitumor effect and the cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor BM-1197 in DCBCL and Burkitt lymphoma cells. Methods: CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using the caspase-3/ caspase-9 activity kit. Western blotting analysis was performed to evaluate the change of protein expression. The functional analysis was evalueated via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. Results: We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells which harbor Bcl-2 and Bcl-xL high expression in vitro and has synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interaction of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, PUMA/Bcl-2 and induced conformational change in the Bax protein.which results in activation of Bax and release cytochrome c, and activated caspase -9, -3, -7 and finally induce cell apoptosis. Furthermore, our data demonstrates that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. Conclusions: Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo, and provides promising preclinical data for further development of BM-1197 in malignant lymphoma.

Preparation, Characterization and In-vitro Biological Evaluation of Novel Curcumin Derivatives as Cytotoxic and Apoptosis-Inducing Agents

2020 ◽  
Vol 20 ◽  
Author(s):  
Omid K. Arjomandi ◽  
Saiedeh Almasi ◽  
Leila Hosseinzadeh ◽  
Mahboubeh Kavoosi ◽  
Hadi Adibi
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Caspase 3 ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Caspase 9 ◽  
Derivatives Of ◽  
Mcf 7

Background: Curcumin is a natural polyphenol and lead compound of the rhizomes of curcuma longa that it has been widely used for pharmacological activities. Objective: In this study, series of novel derivatives of curcumin, which this group was linked to a 2-amino-4-phenylpyran-3-carbonitrile system, have been synthesized and tested for their antitumor activities in-vitro against a panel of three human cancer cell lines (MCF-7, A2780, and U-87MG). Method: The in-vitro cytotoxic activity of the synthesized compounds was tested on three cancer cell lines (MCF-7, A2780, and U87MG) using MTT colorimetric assay. Meanwhile, the ability of the active compounds to induce apoptosis in cancer cells was investigated by examination of caspase-3 and caspase-9 and mitochondrial membrane potential assay. Results: Under relatively mild conditions in ethanol, the reaction of a series of substrates afforded the corresponding derivatives of curcumin mostly in good yields (13 analogues, 48-94% yields). Bioassay results indicated that compounds L6 (para-Bromo), L9 (paraNitro) and L12 (meta-Methoxy) were the most active members in this study demonstrating potent activities against A2780 cancer cells and experimental results of fluorescent staining and flow cytometry analysis revealed that L6 and L9 could induce apoptosis in A2780 cells with apoptosis ratios of about 40% and 46%, respectively at 24 h of treatment at 15.35 µM and 23µM in A2780 cells. On the other hand, they could increase the caspase-3 activity slightly (10%), while had no significant impact on the activities of caspase-9. Conclusion: Those two derivatives could be considered as useful templates for future development to obtain more potent antitumor agents.

scholarly journals Synthesis and Biological Evaluation of Novel Betulin Derivatives with Aromatic Hydrazone Side Chain as Potential Anticancer Agents

2021 ◽  
Author(s):  
Jiafeng Wang ◽  
Jiale Wu ◽  
Yinglong Han ◽  
Jie Zhang ◽  
Yu Lin ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Antitumor Agents ◽  
Biological Evaluation ◽  
Carcinoma Cells ◽  
Side Chain ◽  
Human Carcinoma ◽  
Hct 116 ◽  
Synthesis And Biological Evaluation ◽  
Mcf 7

A series of novel betulin-28-hydrazone derivatives (7a-7o) were synthesized. All compounds were evaluated for their in vitro cytotoxicities in four human carcinoma cells (HepG2, MCF-7, HCT-116 and A549). Among them, compound 7l displayed the most potent cytotoxicity with an IC50 (concentration of the tested compound that inhibits 50% of cell growth) value of 7.37 ± 0.38 μM against MCF-7 cells. The preliminary cellular mechanism studies indicated that compound 7l could induce MCF-7 cells apoptosis. The above findings indicated that compound 7l may be used as a lead compound for antitumor agents with improved efficacy.

scholarly journals A novel Bcl-2 inhibitor, BM-1197, Induces apoptosis in Malignant Lymphoma Cells through the Endogenous Apoptotic Pathway

2019 ◽  
Author(s):  
Yue-Li Sun ◽  
Wen-Qi Jiang ◽  
Qiu-Yun Luo ◽  
Da-Jun Yang ◽  
Yu-Chen Cai ◽  
...  
Keyword(s):  
Malignant Lymphoma ◽  
Caspase 3 ◽  
Caspase 9 ◽  
Antitumor Effects ◽  
Lymphoma Cells ◽  
Dual Inhibitor ◽  
Apoptosis Pathway ◽  
Xenograft Models

Abstract Background: Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family protein can be new strategy for malignant lymphoma treatment. In this study, we investigate the antitumor effect and the cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor BM-1197 in DCBCL and Burkitt lymphoma cells. Methods: CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using the caspase-3/ caspase-9 activity kit. Western blotting analysis was performed to evaluate the change of protein expression. The functional analysis was evalueated via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. Results: We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells which harbor Bcl-2 and Bcl-xL high expression in vitro and has synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interaction of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, PUMA/Bcl-2 and induced conformational change in the Bax protein.which results in activation of Bax and release cytochrome c, and activated caspase -9, -3, -7 and finally induce cell apoptosis. Furthermore, our data demonstrates that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. Conclusions: Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo, and provides promising preclinical data for further development of BM-1197 in malignant lymphoma.

Design, Synthesis and In Vitro Anti-Cancer Evaluation of Novel Derivatives of 2-(2-Methyl-1,5-diaryl-1H-pyrrol-3-yl)-2-oxo-N-(pyridin-3- yl)acetamide

2020 ◽  
Vol 16 (3) ◽  
pp. 340-349
Author(s):  
Ebrahim S. Moghadam ◽  
Farhad Saravani ◽  
Ernest Hamel ◽  
Zahra Shahsavari ◽  
Mohsen Alipour ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Peripheral Neuropathy ◽  
Cell Line ◽  
Normal Cell ◽  
Caspase 3 ◽  
Annexin V ◽  
Normal Cell Line ◽  
Anti Cancer ◽  
Mcf 7

Objective: Several anti-tubulin agents were introduced for the cancer treatment so far. Despite successes in the treatment of cancer, these agents cause toxic side effects, including peripheral neuropathy. Comparing anti-tubulin agents, indibulin seemed to cause minimal peripheral neuropathy, but its poor aqueous solubility and other potential clinical problems have led to its remaining in a preclinical stage. Methods: Herein, indibulin analogues were synthesized and evaluated for their in vitro anti-cancer activity using MTT assay (on the MCF-7, T47-D, MDA-MB231 and NIH-3T3 cell lines), annexin V/PI staining assay, cell cycle analysis, anti-tubulin assay and caspase 3/7 activation assay. Results: One of the compounds, 4a, showed good anti-proliferative activity against MCF-7 cells (IC50: 7.5 μM) and low toxicity on a normal cell line (IC50 > 100 μM). All of the tested compounds showed lower cytotoxicity on normal cell line in comparison to reference compound, indibulin. In the annexin V/PI staining assay, induction of apoptosis in the MCF-7 cell line was observed. Cell cycle analysis illustrated an increasing proportion of cells in the sub-G-1 phase, consistent with an increasing proportion of apoptotic cells. No increase in G2/M cells was observed, consistent with the absence of anti-tubulin activity. A caspase 3/7 assay protocol showed that apoptosis induction by more potent compounds was due to activation of caspase 3. Conclusion: Newly synthesized compounds exerted acceptable anticancer activity and further investigation of current scaffold would be beneficial.

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