Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition

The global cancer burden remains a serious concern with the alarming incidence of one in eight men and one in eleven women dying in developing countries. This situation is aggravated by the multidrug resistance (MDR) of cancer cells that hampers chemotherapy. In this study, the cytotoxicity of the methanol extract (HRB), fractions (HRBa, HRBb, and HRBa1-5), and compounds from the bark of Hypericum roeperianum (HRB) was evaluated towards a panel of 9 cancer cell lines. The mode of action of the HRB and trichadonic acid (1) was also studied. Column chromatography was applied to isolate the constituents of HRB. The cytotoxicity of botanicals and phytochemicals was evaluated by the resazurin reduction assay (RRA). Caspase-Glo assay was used to evaluate the activity of caspases, and reactive oxygen species (ROS) (H2DCFH-DA) were assessed by flow cytometry. Phytochemicals isolated from HRB were trichadonic acid (1), fridelan-3-one (2), 2-hydroxy-5-methoxyxanthone (3), norathyriol (4), 1,3,5,6-tetrahydroxyxanthone (5), betulinic acid (6), 3′-hydroxymethyl-2′-(4″-hydroxy-3″,5″-dimethoxyphenyl)-5′,6′:5,6-(6,8-dihydroxyxanthone)-1′,4′-dioxane (7), and 3′-hydroxymethyl-2′-(4″-hydroxy-3″,5″-dimethoxyphenyl)-5′,6′:5,6-(xanthone)-1′,4′-dioxane (8). Botanicals HRB, HRBa, HRBa2-4, HRBb, and doxorubicin displayed cytotoxic effects towards the 9 tested cancer cell lines. The recorded IC50 values ranged from 11.43 µg/mL (against the P-glycoprotein (gp)-overexpressing CEM/ADR5000 leukemia cells) to 26.75 µg/mL (against HCT116 (p53+/+) colon adenocarcinoma cells) for the crude extract HRB. Compounds 1, 5, and doxorubicin displayed cytotoxic effects towards the 9 tested cancer cell lines with IC50 values varying from 14.44 µM (against CCRF-CEM leukemia cells) to 44.20 µM (against the resistant HCT116 (p53−/−) cells) for 1 and from 38.46 µM (against CEM/ADR5000 cells) to 112.27 µM (against the resistant HCT116 (p53−/−) cells) for 5. HRB and compound 1 induced apoptosis in CCRF-CEM cells. The apoptotic process was mediated by enhanced ROS production for HRB or via caspases activation and enhanced ROS production for compound 1. This study demonstrated that Hypericum roeperianum is a potential source of cytotoxic phytochemicals such as trichadonic acid and could be further exploited in cancer chemotherapy.

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Insights into histone deacetylase inhibitors-induced apoptosis in cancer cell lines

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(08)71284-9 ◽

2008 ◽

Vol 6 (9) ◽

pp. 28

Author(s):

P. Ruiz-Rico ◽

M.P. Menéndez-Gutiérrez ◽

E. Carrasco-García ◽

R. Martínez-Mira ◽

L. Rocamora-Reverte ◽

...

Keyword(s):

Histone Deacetylase ◽

Cell Lines ◽

Cancer Cell ◽

Histone Deacetylase Inhibitors ◽

Cancer Cell Lines ◽

Induced Apoptosis

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Species D Adenoviruses as Oncolytic Viral Vectors

Viruses ◽

10.3390/v12121399 ◽

2020 ◽

Vol 12 (12) ◽

pp. 1399

Author(s):

Brianna L. Bullard ◽

Brigette N. Corder ◽

Eric A. Weaver

Keyword(s):

Blood Coagulation ◽

Cell Lines ◽

Cancer Cell ◽

Neutralizing Antibodies ◽

Coagulation Factor ◽

Cancer Cell Lines ◽

Factor X ◽

Multiple Cancer ◽

Iodide Uptake ◽

Oncolytic Adenoviruses

Oncolytic adenoviruses (Ad) have shown promising results in the therapeutic treatment of cancer. Ad type 5 (Ad5) is the most extensively utilized Ad type. However, several limitations exist to using Ad5 as an oncolytic virus, including high levels of anti-Ad5 neutralizing antibodies in the population, binding of the Ad5 hexon to blood coagulation factor X leading to liver sequestration and toxicity, and reduced expression of the primary receptor CAR on many tumors. Here, we use in vitro methods to explore the oncolytic potential of four alternative Ad types (Ad26, 28, 45, and 48) belonging to the species D Ad subgroup and developed replication-competent species D Ads expressing the human sodium iodide symporter protein (hNIS) for combination radiovirotherapy. We evaluated the species D Ad vectors transduction, replication, cytotoxicity, and gene expression in six different cancer cell lines. Species D Ads showed the greatest transduction and cytotoxic killing in the SKBR3 breast cancer cells, followed by 293, A549, and HepG2 cells, however the cytotoxicity was less than the wild type Ad5 virus. In contrast, species D Ads showed limited transduction and cytotoxicity in the Hela and SKOV3 cancer cell lines. These species D Ad vectors also successfully expressed the hNIS gene during infection leading to increased iodide uptake in multiple cancer cell lines. These results, the low seroprevalence of anti-species D antibodies, and the lack of binding to blood coagulation FX, support further exploration of species D Ads as alternative oncolytic adenoviruses against multiple types of cancer.

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Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays

International Journal of Molecular Sciences ◽

10.3390/ijms21010161 ◽

2019 ◽

Vol 21 (1) ◽

pp. 161

Author(s):

Cristian O. Salas ◽

Ana Maria Zarate ◽

Vladimir Kryštof ◽

Jaime Mella ◽

Mario Faundez ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

3D Qsar ◽

Cancer Cell Lines ◽

Neoplastic Cell ◽

Purine Derivatives ◽

Qsar Models ◽

Purine Ring ◽

Induced Apoptosis

We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.

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Novel mechanism of cannabidiol-induced apoptosis in breast cancer cell lines

The Breast ◽

10.1016/j.breast.2018.06.009 ◽

2018 ◽

Vol 41 ◽

pp. 34-41 ◽

Cited By ~ 19

Author(s):

Ahmed S. Sultan ◽

Mona A. Marie ◽

Salah A. Sheweita

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines ◽

Induced Apoptosis

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Metformin Inhibits Gemcitabine Induced Apoptosis in Pancreatic Cancer Cell Lines

Journal of Cancer ◽

10.7150/jca.17972 ◽

2017 ◽

Vol 8 (10) ◽

pp. 1744-1749 ◽

Cited By ~ 7

Author(s):

Dietmar Zechner ◽

Ann-Christin Albert ◽

Florian Bürtin ◽

Brigitte Vollmar

Keyword(s):

Pancreatic Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Cancer Cell Lines ◽

Induced Apoptosis

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Troglitazone Increases the Susceptibility to TRAIL-Induced Apoptosis in Thyroid Cancer Cell Lines

The Korean Journal of Endocrine Surgery ◽

10.16956/kjes.2003.3.2.113 ◽

2003 ◽

Vol 3 (2) ◽

pp. 113

Author(s):

Jin-Woo Park ◽

Orlo H. Clark

Keyword(s):

Thyroid Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Thyroid Cancer Cell ◽

Induced Apoptosis ◽

Thyroid Cancer Cell Lines

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Anti-EpCAM XmAb antibodies with improved cytotoxicity

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.12506 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 12506-12506 ◽

Cited By ~ 1

Author(s):

O. Vafa ◽

S. Kharki ◽

J. Vielmetter ◽

A. Chamberlain ◽

P. Hammond ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Clinical Efficacy ◽

Cancer Cell Lines ◽

In Vitro Cytotoxicity ◽

Binding Assays ◽

Multiple Cancer ◽

Effector Cells ◽

Dependent Cell

12506 Background: The epithelial cell adhesion molecule (EpCAM), also known as epithelial protein 2 (EGP-2) or 17–1A antigen, is a trans-membrane protein expressed on the surfaces of most carcinomas, including those of pancreatic, colorectal, prostate, breast, kidney, lung, and ovarian origins. Moderate affinity antibodies (Abs) such as 17–1A (Kd ∼ 10−7 nM) have been safe in humans albeit with limited clinical efficacy. Attempts to improve clinical efficacy by enhancing antigen affinity (Kd ∼ 10−9 nM) have led to serious clinical toxicity, including pancreatitis. These observations raise the question of whether a moderate affinity Ab with enhanced effector function will be both safe and clinically efficacious. Methods: We applied our proprietary XmAb™ technologies to humanize the 17–1A variable domain and engineer a human IgG1 Fc domain to increase affinity for the activating receptor FcγRIIIa. Ab binding to Ep-CAM or to Fc receptors was tested with Biacore and/or AlphaScreen binding assays. In vitro cytotoxic activity against representative cancer cell lines was measured with Antibody Dependent Cell-mediated Cytotoxicity (ADCC) assays, using human PBMC as effector cells. Results: Humanized anti-EpCAM Abs have affinity for EpCAM similar to the parent 17–1A. Affinity for the activating FcγRIIIa was increased 100-fold relative to a control Ab with an IgG1 Fc domain. As expected, these Abs exhibit dramatically enhanced ADCC against multiple cancer cell lines relative to 17–1A and IgG1 control Abs. Despite their moderate affinity for EpCAM, these novel Abs have in vitro cytotoxicity comparable to the high affinity Ab ING-1. CDC activities of these Abs were similar to chimeric 17–1A. Conclusions: We have demonstrated that antibodies with moderate affinity for EpCAM and increased FcγRIIIa affinity exhibit superior cancer cell killing via an ADCC mechanism. The humanized nature and the increased cytotoxicity of anti-EpCAM XmAb™ antibodies make them promising candidates for clinical development of a novel pan-carcinoma Ab that is superior to 17–1A. [Table: see text]

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Xylopine Induces Oxidative Stress and Causes G2/M Phase Arrest, Triggering Caspase-Mediated Apoptosis by p53-Independent Pathway in HCT116 Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/7126872 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 12

Author(s):

Luciano de Souza Santos ◽

Valdenizia Rodrigues Silva ◽

Leociley Rocha Alencar Menezes ◽

Milena Botelho Pereira Soares ◽

Emmanoel Vilaça Costa ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Lines ◽

Cancer Cell ◽

Caspase 3 ◽

Cancer Cell Lines ◽

Apoptosis Pathway ◽

Phase Arrest ◽

M Phase ◽

Induced Apoptosis ◽

Hct116 Cells

Xylopine is an aporphine alkaloid that has cytotoxic activity to cancer cells. In this study, the underlying mechanism of xylopine cytotoxicity was assessed in human colon carcinoma HCT116 cells. Xylopine displayed potent cytotoxicity in different cancer cell lines in monolayer cultures and in a 3D model of cancer multicellular spheroids formed from HCT116 cells. Typical morphology of apoptosis, cell cycle arrest in the G2/M phase, increased internucleosomal DNA fragmentation, loss of the mitochondrial transmembrane potential, and increased phosphatidylserine externalization and caspase-3 activation were observed in xylopine-treated HCT116 cells. Moreover, pretreatment with a caspase-3 inhibitor (Z-DEVD-FMK), but not with a p53 inhibitor (cyclic pifithrin-α), reduced xylopine-induced apoptosis, indicating induction of caspase-mediated apoptosis by the p53-independent pathway. Treatment with xylopine also caused an increase in the production of reactive oxygen/nitrogen species (ROS/RNS), including hydrogen peroxide and nitric oxide, but not superoxide anion, and reduced glutathione levels were decreased in xylopine-treated HCT116 cells. Application of the antioxidant N-acetylcysteine reduced the ROS levels and xylopine-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. In conclusion, xylopine has potent cytotoxicity to different cancer cell lines and is able to induce oxidative stress and G2/M phase arrest, triggering caspase-mediated apoptosis by the p53-independent pathway in HCT116 cells.

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