EXTH-16. LP-184, A NOVEL ALKYLATING AGENT, IS EFFECTIVE IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi166-vi167
Author(s):  
Bachchu Lal ◽  
Aditya Kulkarni ◽  
Joseph McDermott ◽  
Umesh Kathad ◽  
Kishor Bhatia ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Alkylating Agent ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
High Sensitivity ◽  
Complete Regression ◽  
Apparent Permeability ◽  
Clinical Databases

Abstract Temozolomide (TMZ) is currently the most effective standard-of-care chemotherapy based on its ability to prolong survival of patients with newly diagnosed MGMT-methylated GBM. Blood-brain barrier permeable agents effective against TMZ-resistant GBMs (i.e. recurrent GBM, MGMT unmethylated GBM) are desperately needed. Lantern Pharma is currently developing LP-184, a hydroxyurea methyl acylfulvene derivative of irofulven guided by its AI platform RADRⓇ analysis showing that tumor cell sensitivity to LP-184 correlates positively with genes commonly upregulated in GBM and either associated with TMZ resistance (e.g. MGMT, UGDH) or tumor promotion (e.g. EGFR, ANXA2). In an in vitro 3D model that mimics the human BBB, the apparent permeability for LP-184 was 1.53E-04 cm/s at 30 minutes, comparable to 1.72E-04 cm/s for TMZ under identical conditions. LP-184 predominantly alkylates DNA at 3’-adenine predicting insensitivity to MGMT expression. In vitro cell toxicity assays in a panel of GBM cell lines and neurospheres reveal an IC50 range of 30 - 400 nM with the MGMT unmethylated cell line LN-18 being among the most sensitive. A single cycle of LP-184 (4 mg/kg, i.v, every other day X 4 doses) induced rapid and near complete regression of subcutaneous U87 xenografts pre-established in immune-deficient mice and statistically significantly prolonged survival of mice bearing pre-established orthotopic U87 xenografts (p < 0.0001). LP-184-induced DNA damage is associated with synthetic lethality in tumor cell lines with decreased expression of Nucleotide Excision Repair (NER) genes. Furthermore, interrogation of clinical databases for expression of 112 NER genes revealed that 25 - 37% of clinical GBM clusters in a low NER expression subgroup, predicting high sensitivity of low NER GBM subsets to LP-184. These findings identify LP-184 as a promising new alkylating agent and support its further development for GBM therapy.

Synthesis and Cytotoxicity of New Mannich Bases of 6-[3-(3,4,5-Trimetoxyphenyl)-2- propenoyl]-2(3H)-Benzoxazolone

2020 ◽  
Vol 17 (4) ◽  
pp. 512-517
Author(s):  
Ognyan Ivanov Petrov ◽  
Yordanka Borisova Ivanova ◽  
Mariana Stefanova Gerova ◽  
Georgi Tsvetanov Momekov
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Biological Activities ◽  
Human Tumor ◽  
Mannich Bases ◽  
In Vitro Cytotoxicity ◽  
Tumor Cell Lines ◽  
Human Tumor Cell ◽  
Human Tumor Cell Lines

Background: Chemotherapy is one of the mainstays of cancer treatment, despite the serious side effects of the clinically available anticancer drugs. In recent years increasing attention has been directed towards novel agents with improved efficacy and selectivity. Compounds with chalcone backbone have been reported to possess various biological activities such as anticancer, antimicrobial, anti-inflammatory, analgesic, antioxidant, etc. It was reported that aminomethylation of hydroxy chalcones to the corresponding Mannich bases increased their cytotoxicity. In this context, our interest has been focused on the design and synthesis of the so-called multi-target molecules, containing two or more pharmacophore fragments. Methods: A series of Mannich bases were synthesized by the reaction between 6-[3-(3,4,5- trimethoxyphenyl)-2-propenoyl]-2(3Н)-benzoxazolone, formaldehyde, and a secondary amine. The structures of the compounds were confirmed by elemental analysis, IR and NMR spectra. The new Mannich bases were evaluated for their in vitro cytotoxicity against a panel of human tumor cell lines, including BV-173, SKW-3, K-562, HL-60, HD-MY-Z and MDA-MB-231. The effects of selected compounds on the cellular levels of glutathione (GSH) were determined. Results: The new compounds 4a-e exhibited concentration-dependent cytotoxic effects at micromolar concentrations in MTT-dye reduction assay against a panel of human tumor cell lines, similar to those of starting chalcone 3. The tested agents led to concentration - dependent depletion of cellular GSH levels, whereby the effects of the chalcone prototype 3 and its Mannich base-derivatives were comparable. Conclusion: The highest chemosensitivity to the tested compounds was observed in BV- 173followed by SKW-3 and HL-60 cell lines.

Cytotoxic Effect of Brassica oleracea Extract on two Tumor Cell Lines in vitro

2013 ◽  
Vol 16 (1) ◽  
pp. 137-142
Author(s):  
Farooq I. Mohammed ◽  
◽  
Farah T. Abdullah ◽  
Shaimaa Y. Abdulfttah ◽  
◽  
...  
Keyword(s):  
Tumor Cell ◽  
Brassica Oleracea ◽  
Cell Lines ◽  
Cytotoxic Effect ◽  
Tumor Cell Lines

scholarly journals Oncolytic peptides DTT-205 and DTT-304 induce complete regression and protective immune response in experimental murine colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Karianne Giller Fleten ◽  
J. Johannes Eksteen ◽  
Brynjar Mauseth ◽  
Ketil André Camilio ◽  
Terje Vasskog ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Cell Lines ◽  
Checkpoint Inhibitors ◽  
Inhibitory Effect ◽  
Systemic Effect ◽  
Intratumoral Injection ◽  
Complete Regression ◽  
Future Drug

AbstractOncolytic peptides represent a novel, promising cancer treatment strategy with activity in a broad spectrum of cancer entities, including colorectal cancer (CRC). Cancer cells are killed by immunogenic cell death, causing long-lasting anticancer immune responses, a feature of particular interest in non-immunogenic CRC. Oncolytic peptides DTT-205 and DTT-304 were administered by intratumoral injection in subcutaneous tumors established from murine CRC cell lines CT26 and MC38, and complete regression was obtained in the majority of animals. When cured animals were rechallenged by splenic injection of tumor cells, 1/23 animals developed liver metastases, compared to 19/22 naïve animals. Treatment with both peptides was well tolerated, but monitoring post-injection hemodynamic parameters in rats, less extensive changes were observed with DTT-205 than DTT-304, favoring DTT-205 for future drug development. DTT-205 was subsequently shown to have strong in vitro activity in a panel of 33 cancer cell lines. In conclusion, both peptides exerted a strong inhibitory effect in two immunocompetent CRC models and induced a systemic effect preventing development of liver metastases upon splenic rechallenge. If a similar effect could be obtained in humans, these drugs would be of particular interest for combinatory treatment with immune checkpoint inhibitors in metastatic CRC.

scholarly journals Pharmacoinformatics and Preclinical Studies of NSC765690 and NSC765599, Potential STAT3/CDK2/4/6 Inhibitors with Antitumor Activities against NCI60 Human Tumor Cell Lines

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 92
Author(s):  
Bashir Lawal ◽  
Yen-Lin Liu ◽  
Ntlotlang Mokgautsi ◽  
Harshita Khedkar ◽  
Maryam Rachmawati Sumitra ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Tumor ◽  
Cancer Cell Lines ◽  
Tumor Cell Lines ◽  
Human Tumor Cell ◽  
Human Tumor Cell Lines ◽  
Anti Cancer

Signal transducer and activator of transcription 3 (STAT3) is a transcriptional regulator of a number of biological processes including cell differentiation, proliferation, survival, and angiogenesis, while cyclin-dependent kinases (CDKs) are a critical regulator of cell cycle progression. These proteins appear to play central roles in angiogenesis and cell survival and are widely implicated in tumor progression. In this study, we used the well-characterized US National Cancer Institute 60 (NCI60) human tumor cell lines to screen the in vitro anti-cancer activities of our novel small molecule derivatives (NSC765690 and NSC765599) of salicylanilide. Furthermore, we used the DTP-COMPARE algorithm and in silico drug target prediction to identify the potential molecular targets, and finally, we used molecular docking to assess the interaction between the compounds and prominent potential targets. We found that NSC765690 and NSC765599 exhibited an anti-proliferative effect against the 60 panels of NCI human cancer cell lines, and dose-dependent cytotoxic preference for NSCLC, melanoma, renal, and breast cancer cell lines. Protein–ligand interactions studies revealed that NSC765690 and NSC765599 were favored ligands for STAT3/CDK2/4/6. Moreover, cyclization of the salicylanilide core scaffold of NSC765690 mediated its higher anti-cancer activities and had greater potential to interact with STAT3/CDK2/4/6 than did NSC765599 with an open-ring structure. NSC765690 and NSC765599 met the required safety and criteria of a good drug candidate, and are thus worthy of further in-vitro and in-vivo investigations in tumor-bearing mice to assess their full therapeutic efficacy.

Evaluation of ponatinib in vitro effect in three canine mast cell tumor cell lines expressing FGFR-1, PDGFR-α, and VEGFR-2

2021 ◽  
Vol 269 ◽  
pp. 105621
Author(s):  
C.J. Fisher ◽  
A.T. Lejeune ◽  
M.J. Dark ◽  
O.M. Hernandez ◽  
K. Shiomitsu
Keyword(s):  
Mast Cell ◽  
Tumor Cell ◽  
Cell Lines ◽  
Cell Tumor ◽  
Tumor Cell Lines ◽  
Mast Cell Tumor ◽  
Canine Mast Cell Tumor ◽  
Vitro Effect

Synthesis and Characterization of New Palladium(II) Complexes with Ligands Derived from Furan-2-carbaldehyde and Benzaldehyde Thiosemicarbazone and their in vitro Cytotoxic Activities against Various Human Tumor Cell Lines

2010 ◽  
Vol 65 (10) ◽  
pp. 1271-1278 ◽  
Author(s):  
Wilfredo Hernández ◽  
Juan Paz ◽  
Fernando Carrasco ◽  
Abraham Vaisberg ◽  
Jorge Manzur ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Human Tumor ◽  
Myelogenous Leukemia ◽  
Cytotoxic Activities ◽  
Spectroscopic Techniques ◽  
Tumor Cell Lines ◽  
Human Tumor Cell ◽  
Human Tumor Cell Lines

With the ligands 4-phenyl-1-(furan-2-carbaldehyde)thiosemicarbazone, HTSC1, (1), 4-phenyl-1- (5´-phenyl-furan-2-carbaldehyde)thiosemicarbazone, HTSC2 (2), o-methoxy-benzaldehydethiosemicarbazone, HTSC3 (3), and o-cyano-benzaldehydethiosemicarbazone, HTSC4 (4), the corresponding palladium(II) complexes, Pd(TSC1)2 (5), Pd(TSC2)2 (6), Pd(TSC3)2 (7), and Pd(TSC4)2 (8) were synthesized and characterized by elemental analysis and spectroscopic techniques. The crystal structure of Pd(TSC3)2 (7) was determined by single-crystal X-ray diffraction. Complex 7 shows a squareplanar geometry, where two deprotonated ligands are coordinated to the PdII center through the nitrogen and sulfur atoms in a trans arrangement. In vitro antitumor studies against different human tumor cell lines have revealed that the palladium(II) complexes 5- 8 are more cytotoxic (IC50 values in the range of 0.21 - 3.79 μM) than their corresponding ligands (1 - 4) (> 60 μM). These results indicate that the antiproliferative activity is enhanced when thiosemicarbazone ligands are coordinated to the metal. Among the studied palladium(II) complexes, 8 exhibits high antitumor activity on K562 chronic myelogenous leukemia cells with a low value of the inhibitory concentration (IC50 = 0.21 μM).

Activation of the heat shock transcription factor by hypoxia in normal and tumor cell lines in vivo and in vitro

1992 ◽  
Vol 23 (4) ◽  
pp. 891-897 ◽  
Author(s):  
Amato J. Giaccia ◽  
Elizabeth A. Auger ◽  
Albert Koong ◽  
David J. Terris ◽  
Andrew I. Minchinton ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Heat Shock ◽  
Tumor Cell ◽  
Cell Lines ◽  
Heat Shock Transcription Factor ◽  
Tumor Cell Lines

scholarly journals Rapid Generation of Single-Tumor Spheroids for High-Throughput Cell Function and Toxicity Analysis

2006 ◽  
Vol 11 (8) ◽  
pp. 922-932 ◽  
Author(s):  
Andrea Ivascu ◽  
Manfred Kubbies
Keyword(s):  
Tumor Cell ◽  
Suspension Culture ◽  
Cell Lines ◽  
Cell Function ◽  
Tumor Cell Lines ◽  
Proliferating Cells ◽  
Basement Membrane Extract ◽  
Rapid Generation ◽  
Size Heterogeneity

Spheroids are widely used in biology because they provide an in vitro 3-dimensional (3D) model to study proliferation, cell death, differentiation, and metabolism of cells in tumors and the response of tumors to radiotherapy and chemotherapy. The methods of generating spheroids are limited by size heterogeneity, long cultivation time, or mechanical accessibility for higher throughput fashion. The authors present a rapid method to generate single spheroids in suspension culture in individual wells. A defined number of cells ranging from 1000 to 20,000 were seeded into wells of poly-HEMA-coated, 96-well, round-or conical-bottom plates in standard medium and centrifuged for 10 min at 1000 g. This procedure generates single spheroids in each well within a 24-h culture time with homogeneous sizes, morphologies, and stratification of proliferating cells in the rim and dying cells in the core region. Because a large number of tumor cell lines form only loose aggregates when cultured in 3D, the authors also performed a screen for medium additives to achieve a switch from aggregate to spheroid morphology. Small quantities of the basement membrane extract Matrigel, added to the culture medium prior to centrifugation, most effectively induced compact spheroid formation. The compact spheroid morphology is evident as early as 24 h after centrifugation in a true suspension culture. Twenty tumor cell lines of different lineages have been used to successfully generate compact, single spheroids with homogenous size in 96-well plates and are easily accessible for subsequent functional analysis.

Pre-clinical evaluation of PV-10 for in vitro anti-tumor activity in refractory and high-risk adult solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14544-e14544
Author(s):  
Son Tran ◽  
Satbir Thakur ◽  
Mohit Jain ◽  
Chunfen Zhang ◽  
Aru Narendran
Keyword(s):  
High Risk ◽  
Tumor Cell ◽  
Solid Tumors ◽  
Cell Lines ◽  
Therapeutic Agent ◽  
Intratumoral Injection ◽  
Tumor Cell Lines ◽  
Clinical Testing ◽  
Anti Tumor Activity

e14544 Background: PV-10 (10% rose bengal disodium; 4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein) is a novel therapeutic agent previously shown to have potent anti-tumor activity following intratumoral injection in melanoma and refractory neuroblastoma, and currently is undergoing clinical testing as a single-agent for refractory metastatic neuroendocrine cancer (NCT02693067) and in combination with checkpoint inhibitors for metastatic melanoma (NCT02557321) and metastatic uveal melanoma (NCT00986661). Given the established clinical efficacy of PV-10 in adult melanoma and hepatic cancers via intratumoral injection, there is a need to evaluate the therapeutic potential of PV-10 in high-risk and refractory adult solid tumors via systemic administration. Our study aims to identify the clinical potential of systemically-delivered PV-10 by first generating prerequisite in vitro data for adult malignancies. Methods: Cytotoxicity assays were performed using the Alamar Blue assay to study the effects of PV-10 in vitro 96-hours post-treatment against a panel of adult solid tumor cell lines derived from breast (MCF-7, T-47D, MDA-MB-231), colorectal (HCT-116, LoVo, T-84), head and neck (CAL-27, Detroit-562, FaDu, UM-SCC-1), and testicular (NCC-IT, NTERA-2, TCAM-2) tissues. Light microscopy and Western blotting were used to investigate apoptosis induction and target modulation in tumor cells after PV-10 treatment. Results: In vitro results from our study demonstrate that PV-10 is cytotoxic at pharmacologically relevant concentrations across the indicated cell lines. Specifically, tumor cell lines originating from testicular tissues were highly sensitive to PV-10 treatment (Mean ± SD IC50: 37.5 ± 16.4 µM; n = 3) compared to breast (117.5 ± 71.0 µM; n = 3), colorectal (64.79 µM; n = 3), and head and neck (106.6 ± 29.2 µM; n = 4) cell lines. Western blot analyses showed dose- and time-dependent activation of pro-apoptotic protein markers in caspase-3 and PARP cleavage, indicating drug-induced apoptosis. Conclusions: This study provides the first pre-clinical results of PV-10 as a novel systemically-delivered therapeutic agent for a range of high-risk and refractory adult solid tumors. Data obtained from our in vitro experiments using a broad repertoire of cell lines that represent diverse molecular and phenotypic subtypes of solid tumors in adults can serve as prerequisite pre-clinical data to establish clinical testing in these populations.

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