Preclinical evaluation of the ETS inhibitor TK216 against relapsed and refractory childhood leukemia.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10033-10033
Author(s):  
Ritul Sharma ◽  
Satbir Thakur ◽  
Mohit Jain ◽  
Chunfen Zhang ◽  
Anne-Marie Langevin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Drug Combination ◽  
Childhood Leukemia ◽  
Sensitive Cell Line ◽  
Pediatric Leukemia ◽  
Drug Synergy ◽  
Molecular Abnormalities ◽  
Anti Cancer ◽  
Combination Studies

10033 Background: Although survival rates have improved in the recent past, relapse and refractory disease remain a significant cause of death in children with leukemia. This calls for an urgent need for the development of novel therapies that could effectively treat leukemias in children. The E26 transformation specific (ETS) family of transcription factors regulate various normal cellular functions but are abnormally expressed in various cancers, including leukemia. TK216 is an ETS inhibitor, that has shown pre-clinical activity and clinical efficacy in solid tumors. In this study, we explore the feasibility of using TK216 as a therapeutic agent for the treatment of high risk refractory pediatric leukemia. Methods: A panel of pediatric leukemia derived cell lines and primary blast cells representing a spectrum of molecular abnormalities seen in pediatric leukemia were treated in vitro with TK216 to determine cytotoxicity. Normal lymphocytes were used as controls and cell viability was determined 72 hours post-treatment by Alamar blue assay. The induction of tumor cell apoptosis and target modulation were detected by Western blotting. Alterations in the cell cycle were assessed by FACS analysis with PI staining. Drug combination studies were carried out with established anti-leukemic agents to identify synergy for greater therapeutic efficiency. Results: TK216 decreased cell viability in leukemia cells compared to normal lymphocyte controls in a dose-dependent manner with variations in sensitivity noted with inherent molecular abnormalities. The IC50 values observed ranged from 0.22 µM for the most sensitive cell line, MV4-11 to 0.95 µM for least sensitive cell line, SUP-B15. Apoptosis induction upon TK216 treatment was confirmed by PARP cleavage and caspase 3 activation. Cell cycle analysis demonstrated increased sub-G1 population of cells after TK216 treatment. A strong correlation between sub-G1 population and sensitivity of the cell line towards TK216 (47% in MV4-11 vs 3.72% in SUP-B15) was observed. Screening of a panel of 200 FDA approved anti-cancer agents in drug combination studies identified potential agents for drug synergy. Significant drug synergy was noted with TK216 in combination with the epigenetic modifier 5-azacytidine and the Bcl-2 inhibitor, Venetoclax. [Combination Index for Venetoclax and TK216, mean = 0.65 for MV4-11 and 0.33 for SUP-B15]. Conclusions: Data from our study demonstrate that the ETS inhibitor TK216 induces apoptosis and cell cycle arrest in pediatric leukemia cells at physiologically relevant concentrations. Our combination studies identified distinct anti-cancer agents that could be used for developing effective drug combination regimens with TK216. Overall, our findings provide essential preclinical data for the consideration of TK216 in early phase clinical trials for the treatment of selected high-risk and refractory childhood leukemia.

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.

scholarly journals Induction of apoptosis by Kola nut extract as a recent and promising treatment strategy for Leukemia

Bionatura ◽  
2021 ◽  
Vol 6 (2) ◽  
pp. 1725-1732
Author(s):  
Hamdah Alsaeedi ◽  
Rowaid Qahwaji ◽  
Talal Qadah
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Leukemia Cell ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
Time Dependent ◽  
Leukemia Cell Line ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
Anti Cancer

Kola nut extracts have recently been reported to contain chemopreventive compounds providing several pharmacological benefits. This study investigated Kola nut extracts' anti-cancer activity on human immortalized myelogenous leukemia cell line K562 through apoptosis and cell cycle arrest. Fresh Kola nuts were prepared as powder and dissolved in DMSO. Different concentrations (50, 100, 150, 200, and 250 μg/ml) of working solutions were prepared. The K562 cells were treated with the different concentrations of Kola nut extract or vehicle control (10% DMSO) followed by incubation at 37°C for 24, 48, and 72 hours, respectively. Treatment activity was investigated in K562 cells; by Resazurin, and FITC/Propidium Iodide and 7-AAD stained cells to evaluate apoptotic cells and the cell cycle's progression. Inhibition of leukemia cell proliferation was observed. The extract effectively induced cell death, early and late apoptosis by approximately 30% after 24 and 48 hours incubation, and an increase in the rate of dead cells by 50% was observed after 72 hours of incubation. Also, cell growth reduction was seen at high dose concentrations (150 and 200 µg/ml), as evident by cell count once treated with Kola nut extract. The total number of apoptotic cells increased from 5.8% of the control group to 27.4% at 250 µg/ml concentration. Moreover, Kola nut extracts' effects on K562 cells increased gradually in a dose and time-dependent manner. It was observed that Kola nut extracts could arrest the cell cycle in the G2/M phase as an increase in the number of cells by 29.8% and 14.6 % were observed from 9.8% and 5.2% after 24 and 48 hours of incubation, respectively. This increase was detected in a dose and time-dependent manner. Kola nut extracts can be used as a novel anti-cancer agent in Leukemia treatment as it has shown significant therapeutic potential and therefore provides new insights in understanding the mechanisms of its action. Keywords: Kola nut extracts, Leukemia, K562 cell line, Apoptosis, Cancer.

scholarly journals Cholecalciferol Inhibits Cell Growth and Induces Apoptosis in the CaSki Cell Line

2020 ◽  
Vol 8 (1) ◽  
pp. 12 ◽  
Author(s):  
Sachin Bhoora ◽  
Yuvelia Pather ◽  
Sumari Marais ◽  
Rivak Punchoo
Keyword(s):  
Cell Cycle ◽  
Vitamin D ◽  
Cell Death ◽  
Cell Count ◽  
Cell Line ◽  
Cervical Cancer Cell Line ◽  
High Dose ◽  
Caski Cell ◽  
Anti Cancer ◽  
Caski Cell Line

Vitamin D has displayed anti-cancer actions in numerous in vitro studies. Here, we investigated the anti-cancer actions of cholecalciferol, a vitamin D precursor, on a metastatic cervical cancer cell line, namely, CaSki. Experimental cultures were incubated for 72 h and treated with cholecalciferol (10–1000 ng/mL). In the present study, cell count, viability, proliferation and cell cycle were analyzed by a crystal violet assay, trypan blue assay, Ki67 proliferation, and a cell cycle assay, respectively. Biomarkers of apoptosis, necrosis, and autophagic cell death were measured by the Caspase 3/7 and Annexin V/7-AAD Muse™ assays, a LC3-II assay, and a lactate dehydrogenase release assay, respectively. The ultrastructural features of cell death were assessed by transmission electron microscopy. A statistical analysis was performed using a one-way ANOVA and Bonferroni’s post-hoc analysis test, and p < 0.05 is considered statistically significant here. The results identify statistical decreases in cell count and viability at high-dose treatments (100 and 1000 ng/mL). In addition, significant increases in apoptotic biochemical markers and apoptotic ultrastructure are shown to be present at high-dose treatments. In conclusion, high-dose cholecalciferol treatments inhibit cell count and viability, which are both mediated by apoptotic induction in the CaSki cell line.

Preclinical Rationale for the Use of the Combined Treatment with the AKT Inhibitor Perifosine and the Multikinase Inhibitor Sorafenib in Hodgkin Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1653-1653
Author(s):  
Silvia Locatelli ◽  
Arianna Giacomini ◽  
Anna Guidetti ◽  
Loredana Cleris ◽  
Michele Magni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Line ◽  
Cell Lines ◽  
Drug Combination ◽  
Akt Inhibitor ◽  
Sorafenib Treatment ◽  
Responsive Cell

Abstract Abstract 1653 Introduction: A significant proportion of Hodgkin lymphoma (HL) patients refractory to first-line chemotherapy or relapsing after autologous transplantation are not cured with currently available treatments and require new treatments. The PI3K/AKT and RAF/MEK/ERK pathways are constitutively activated in the majority of HL. These pathways can be targeted using the AKT inhibitor perifosine (Æterna Zentaris GmBH, Germany, EU), and the RAF/MEK/ERK inhibitor sorafenib (Nexavar®, Bayer, Germany, EU). We hypothesized that perifosine in combination with sorafenib might have a therapeutic activity in HL by overcoming the cytoprotective and anti-apoptotic effects of PI3K/Akt and RAF/MEK/ERK pathways. Since preclinical evidence supporting the anti-lymphoma effects of the perifosine/sorafenib combination are still lacking, the present study aimed at investigating in vitro and in vivo the activity and mechanism(s) of action of this two-drug combination. METHODS: Three HL cell lines (HD-MyZ, L-540 and HDLM-2) were used to investigate the effects of perifosine and sorafenib using in vitro assays analyzing cell growth, cell cycle distribution, gene expression profiling (GEP), and apoptosis. Western blotting (WB) experiments were performed to determine whether the two-drug combination affected MAPK and PI3K/AKT pathways as well as apoptosis. Additionally, the antitumor efficacy and mechanism of action of perifosine/sorafenib combination were investigated in vivo in nonobese diabetic/severe combined immune-deficient (NOD/SCID) mice. RESULTS: While perifosine and sorafenib as single agents exerted a limited activity against HL cells, exposure of HD-MyZ and L-540 cell lines, but not HDLM-2 cells, to perifosine/sorafenib combination resulted in synergistic cell growth inhibition (40% to 80%) and cell cycle arrest. Upon perifosine/sorafenib exposure, L-540 cell line showed significant levels of apoptosis (up to 70%, P ≤.0001) associated with severe mitochondrial dysfunction (cytochrome c, apoptosis-inducing factor release and marked conformational change of Bax accompanied by membrane translocation). Apoptosis induced by perifosine/sorafenib combination did not result in processing of caspase-8, -9, -3, or cleavage of PARP, and was not reversed by the pan-caspase inhibitor Z-VADfmk, supporting a caspase-independent mechanism of apoptosis. In responsive cell lines, WB analysis showed that anti-proliferative events were associated with dephosphorylation of MAPK and PI3K/Akt pathways. GEP analysis of HD-MyZ and L-540 cell lines, but not HDLM-2 cells indicated that perifosine/sorafenib treatment induced upregulation of genes involved in amino acid metabolism and downregulation of genes regulating cell cycle, DNA replication and cell death. In addition, in responsive cell lines, perifosine/sorafenib combination strikingly induced the expression of tribbles homologues 3 (TRIB3) both in vitro and in vivo. Silencing of TRIB3 prevented cell growth reduction induced by perifosine/sorafenib treatment. In vivo, the combined perifosine/sorafenib treatment significantly increased the median survival of NOD/SCID mice xenografted with HD-MyZ cell line as compared to controls (81 vs 45 days, P ≤.0001) as well as mice receiving perifosine alone (49 days, P ≤.03) or sorafenib alone (54 days, P ≤.007). In mice bearing subcutaneous nodules generated by HD-MyZ and L-540 cell lines but not HDLM-2 cell line, perifosine/sorafenib treatment induced significantly increased levels of apoptosis (2- to 2.5-fold, P ≤.0001) and necrosis (2- to 8-fold, P ≤.0001), as compared to controls or treatment with single agents. CONCLUSIONS: Perifosine/sorafenib combination resulted in potent anti-HL activity both in vitro and in vivo. These results warrant clinical evaluation in HL patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Evaluation of Cytotoxicity and Apoptotic behavior of Cerium Oxide/Zinc Oxide/ Graphene Oxide in HeLa and VERO cell Lines

2021 ◽  
Author(s):  
saranya J ◽  
BS Sre ◽  
M Arivanandan ◽  
K Bhuvaneswari ◽  
S Sherin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Zinc Oxide ◽  
Graphene Oxide ◽  
Hela Cell ◽  
Cell Line ◽  
Cerium Oxide ◽  
Cell Lines ◽  
Morphological Properties ◽  
Hela Cell Lines ◽  
Anti Cancer

Abstract Using the ultrasonic approach, we produced a morphology involving cerium oxide/ Zinc oxide/graphene oxide (CeO2/ZnO/GO) nanocomposite-based system. The developed nanocomposite was examined using X-Ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and field emission scanning electron microscopy (FESEM). The average crystallite size was found to be 11.44 nm, as determined by XRD. FTIR analysis was used to confirm the existence of functional groups. FESEM was used to verify the morphological properties of CeO2/ZnO/GO. The micromorphology of CeO2/ZnO/GO nanocomposite reveals a smoother sheet-like structure. In addition, using an antiproliferative assay test, the developed nanosystem was evaluated for its scavenging anti-cancer capability against HeLa cell lines at various doses and incubation intervals. In our investigation, the effective IC50 concentration was reported to be 62.5 µg/ml at 72 h. Further, the developed nanosystem was evaluated for its killing efficacy against normal cell line. To identify apoptosis-associated alterations of cell membranes throughout the apoptosis process, a dual acridine orange/ethidium bromide (AO/EB) fluorescent staining was done using CeO2/ZnO/GO nanocomposite at three specific concentrations. The quantitative analysis was carried out using flow cytometry (FACS study) to determine the cell cycle during which the greatest number of HeLa cells were destroyed. According to the results of the FACS investigation, maximum cell cycle has taken place in P2, P4.As a result, the newly designed CeO2/ZnO/GO hybrid has demonstrated improved anti-cancer efficacy against the HeLa cell line, making it a better therapeutic agent for cervical cancer detection.

Application of Proteomics in the Search for Novel Proteins Associated with the Anti-cancer Effect of the Synthetic Cyclin-dependent Kinases Inhibitor, Bohemine

2002 ◽  
Vol 1 (4) ◽  
pp. 247-256 ◽  
Author(s):  
Hana Kovarova ◽  
Petr Halada ◽  
Petr Man ◽  
Petr Dzubak ◽  
Marian Hajduch
Keyword(s):  
Mass Spectrometry ◽  
Cell Cycle ◽  
Protein Expression ◽  
Cell Line ◽  
Metabolic Pathways ◽  
Kinase Inhibitor ◽  
A549 Cells ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Anti Cancer

The purpose of this study was to use the proteomics approach, which is based on high resolution two-dimensional electrophoresis coupled with multivariate correspondence analysis and mass spectrometry, to classify objectively the biochemical basis of the anti-cancer activity of the synthetic cyclin-dependent kinase inhibitor, bohemine (BOH). The changes in the cell cycle and corresponding protein composition of the A549 human lung adenocarcinoma cell line after treatment with BOH were evaluated and proteins differentially expressed in the BOH treated A549 cells, compared to the untreated A549 counterparts, were selected. Thirteen of these candidate proteins associated with the drug effects in vitro were identified by mass spectrometry. Many of these proteins fall into one of three functional categories: i) metabolic pathways (glycolysis, nucleic acid synthesis and NADPH production), ii) stress response and protein folding, and iii) cytoskeleton and exocytosis. Changes in protein expression patterns corresponded to a higher resistance of A549 lung carcinoma cells to BOH when compared to the CEM leukaemia cell line. These protein changes reflect a fine balance of the resistant versus the susceptible phenotype in response to the drug. Since BOH is a selective cyclin-dependent kinase inhibitor, changes in the protein expression pattern can be more generally associated with cell cycle regulation as evidenced by inhibition of cell cycling in A549 cells. Our conclusions further underline the importance of cell cycle control in both the cellular signalling and metabolic pathways.

Preclinical Studies of Cytotoxicity, Drug Synergy and Biological Correlates of Clofarabine Against Infant Leukemia Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4342-4342
Author(s):  
Aarthi Jayanthan ◽  
Anjali Singh ◽  
Victor A Lewis ◽  
Aru Narendran
Keyword(s):  
Growth Inhibition ◽  
Cell Lines ◽  
Drug Combination ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Preclinical Studies ◽  
Drug Synergy ◽  
Mitochondrial Integrity ◽  
Combination Studies ◽  
Infant Leukemia

Abstract Abstract 4342 Preclinical Studies of Cytotoxicity, Drug Synergy and Biological Correlates of Clofarabine Against Infant Leukemia Cells. Infants with leukemia, specifically those who relapse on frontline therapy, are extremely difficult to cure and are candidates for novel therapies that induce remission, allowing them to proceed to transplantation. The unique molecular, growth and chemoresistance properties of infant acute lymphoblastic leukemia (iALL) allow for focused preclinical studies within this group. Clofarabine (Clolar), an anti-neoplastic purine nucleoside analog, has shown significant efficacy in older children with refractory lymphoblastic leukemia. Its safety profile has more recently been established in Phase I and II single-agent trials. In addition to its anti-metabolite action, clofarabine appears to disrupt the integrity of mitochondrial membranes and activates pathways of programmed cell death, adding to its theoretical potential to synergize with agents that interfere with mitochondrial integrity. Methods: Primary leukemic cells, cell lines derived from iALL patients and cell lines carrying the molecular abnormalities commonly found in iALL, were used in this study (n=10). Karyotypic abnormalities of these cells include: t(11;19) (q23;p13), t(9;11)(p21;q23) and t(4;11)(q21;q23). With respect to Flt-3 expression, cell lines demonstrating wild-type, internal tandem duplication (ITD) and over-expression phenotypes were also included in this panel. Primary infant AML samples (n=2) and the infant AML cell line TIB-202 (THP-1) containing the t(9;11)(p21;q23) rearrangement and MLL-AF9 fusion gene were also included. ALL cell lines derived from pediatric patients (n= 5) were evaluated in parallel. Stromal cells established from normal bone marrow specimens and peripheral blood mononuclear cells were evaluated under identical conditions for assessment of non-specific toxicity. An increasing concentration of clofarabine was added to leukemic and control cells (104 cells per well, in 96 well plates) cell lines. Over the following four days, cell growth inhibition was measured by the Alamar blue assay. For drug combination studies, leukemia cells were incubated with a panel of conventional and targeted therapeutic agents (n=12) alone or in combination with clofarabine (IC10 or IC25 concentrations). Growth inhibition under each condition was measured and combination indices were calculated according to established methods. Induction of apoptosis and the release of mitochondrial mediators were measured by Western blot analysis. Alteration in mitochondrial integrity was evaluated by immunocytochemistry for fluorescent labeled anti-mitochondrial Hsp70 and real-time imaging. Results and Discussion: Clofarabine inhibited growth of all iALL cells tested with IC50 values ranging from 0.1 μ M to 0.01 μ M. Primary iAML cells were found to be most sensitive to clofarabine. For iALL cell lines the highest IC50 value was found in Bel-1 cells, expressing a t(4;11)(q21;q23) karyotype. Drug combination studies showed significant synergy with 17-AAG (Hsp90 inhibitor, CI 0.7), sorafenib (CI 0.12), bortezomib (CI 0.3) and rapamycin (CI 0.2). No drug combinability was noted, with conventional alkylating agents and antimetabolites. Interestingly, the therapeutic opioid methadone (D,L-methadone hydrochloride), used extensively in the treatment of cancer pain and opioid addiction, showed significant synergy with clofarabine at low concentrations (CI 0.74, range 0.66 – 0.79 μ M). Incubation of cells with clofarabine (IC25) for 48 hours resulted in detectable activation of caspase 9 and cleavage of PARP. We demonstrate the ability of clofarabine to induce cytotoxicity against a panel of leukemia cells that carry the molecular aberrations and growth properties seen in iALL. We also present data on the biological correlates and synergistic effects of clofarabine with other anti-leukemic agents. Of particular interest is the synergy with methadone, which has been shown previously to affect mitochondrial activity in leukemia cells. Data presented in study provide key initial data to construct effective xenograft studies and to formulate a clofarabine based treatment protocol for iALL in the near future. Disclosures: Narendran: Genzyme Canada: Research Funding.

scholarly journals DNA-damage and cell cycle arrest initiated anti-cancer potency of super tiny carbon dots on MCF7 cell line

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sinem Şimşek ◽  
Ayça Aktaş Şüküroğlu ◽  
Derya Yetkin ◽  
Belma Özbek ◽  
Dilek Battal ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cell Line ◽  
Carbon Dots ◽  
Mcf7 Cell ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Mcf7 Cell Line

Design, Synthesis and Bioactivity Evaluation of Novel Chalcone Derivatives Possessing Tryptophan Moiety with Dual Activities of Anti-cancer and Partially Restoring the Proliferation of Normal Kidney Cells Pre-treated with Cisplatin

2021 ◽  
Vol 21 ◽  
Author(s):  
Meng He ◽  
Mingjun Yu ◽  
Chao Li ◽  
Xiaoming Meng ◽  
Jiamin Su ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Normal Cell ◽  
Kidney Cells ◽  
Normal Kidney ◽  
Normal Cell Line ◽  
Chalcone Derivatives ◽  
Anti Cancer ◽  
Anti Inflammatory ◽  
Cancer Activity

Background: Chalcone is a broad-spectrum natural product with anti-cancer and anti-inflammatory activities. However, low potency, low selectivity, and serious side effects limit its druggability. L-Tryptophan is an essential precursor molecule of an anti-cancer active substance. Also, the indole moiety inhibits the proliferation of tumor cells by binding to colchicine sites. A decrease in kidney cell activity caused by kidney inflammation is the primary side effect of cancer therapy. Objective: The purpose of this work was to design, synthesize, and perform bioactivity evaluation of novel chalcone derivatives possessing tryptophan moiety with dual activities of anti-cancer and partially restoring the proliferation of normal kidney cells pre-treated with cisplatin. Methods: A series of novel chalcone derivatives possessing tryptophan moiety (5a-5g, 6a-6o) were designed, synthesized, and evaluated for anti-cancer activity against four cancer cell lines (gastric (HGC-27), colon (HCT-116), prostate (PC-3), and lung (A549)), and a human normal cell line (gastric mucosal epithelial (GES-1)). The activity of restoring the proliferation of normal kidney cells pre-treated with cisplatin was evaluated by MTT assay. Cell cycle, apoptosis, and apoptosis proteins (Bax and Bcl-2) were used to evaluate the anti-cancer mechanism of the most potent compound. Moreover, a docking study was performed to explain the high anti-cancer activity of 6n. The expressions of TNF-α, IL-6, and MCP-1 were detected by ELISA. Results: Most of the compounds exhibited high anti-cancer activity against the HGC-27 cell line and exhibited low toxicity against the normal cell line. Based on three rounds of a structure optimization, 6n was discovered as the most potent compound against HGC-27 cells with an IC50 value of 2.02 μM and an SI value of 28.47. Further studies demonstrated that 6n could induce cell cycle arrest at the G2/M phase and the apoptosis of the HGC-27 cell line by reducing the expression of Bcl-2 and improving the expression level of Bax. Molecular docking result displayed 6n bound to the colchicine site. At the same time, 6n also exhibited moderate activity of restoring the proliferation of normal kidney cells pre-treated with cisplatin by reducing the expression of inflammatory substances. Conclusion: Our findings collectively suggested that 6n should be further studied as a potential anti-cancer agent that could partially restore the proliferation of normal kidney cells pre-treated with cisplatin in gastric cancer patients by an anti-inflammatory pathway.

scholarly journals Anti-Cancer Effect of 3-Hydroxy-β-Ionone Identified from Moringa oleifera Lam. Leaf on Human Squamous Cell Carcinoma 15 Cell Line

Molecules ◽  
2020 ◽  
Vol 25 (16) ◽  
pp. 3563
Author(s):  
Thitiya Luetragoon ◽  
Rungnapa Pankla Sranujit ◽  
Chanai Noysang ◽  
Yordhathai Thongsri ◽  
Pachuen Potup ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Line ◽  
Squamous Cell ◽  
Colony Formation ◽  
Moringa Oleifera ◽  
Leaf Extracts ◽  
Human Squamous Cell Carcinoma ◽  
Anti Cancer

Squamous cell carcinoma is the most common type of head and neck cancer worldwide. Radiation and chemotherapy are general treatments for patients; however, these remedies can have adverse side effects and tumours develop drug resistance. Effective treatments still require improvement for cancer patients. Here, we investigated the anti-cancer effect of Moringa oleifera (MO) Lam. leaf extracts and their fractions, 3-hydroxy-β-ionone on SCC15 cell line. SCC15 were treated with and without MO leaf extracts and their fractions. MTT assay was used to determine cell viability on SCC15. Cell cycle and apoptosis were evaluated by the Muse™ Cell Analyser. Colony formation and wound closure analysis of SCC15 were performed in 6-well plates. Apoptosis markers were evaluated by immunoblotting. We found that Moringa extracts and 3-HBI significantly inhibited proliferation of SCC15. Moreover, they induced apoptosis and cell cycle arrest at G2/M phase in SCC15 compared to the untreated control. MO extracts and 3-HBI also inhibited colony formation and cell migration of SCC15. Furthermore, we observed the upregulation of cleaved caspase-3 and Bax with downregulation of anti-apoptotic Bcl-2, indicating the induction of cancer cell apoptosis. Our results revealed that MO extracts and 3-HBI provided anti-cancer properties by inhibiting progression and inducing apoptosis of SCC15.

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