scholarly journals PPARγInhibitors as Novel Tubulin-Targeting Agents

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-9 ◽  
Author(s):  
Katherine L. Schaefer
Keyword(s):  
Cancer Cell ◽  
Xenograft Model ◽  
Cancer Cell Death ◽  
Microtubule Polymerization ◽  
Therapeutic Benefits ◽  
Murine Xenograft Model ◽  
Microtubule Targeting Agents ◽  
Colorectal Cancer Cell Lines ◽  
Antimicrotubule Drugs

The microtubule-targeting agents (MTAs) are a very successful class of cancer drugs with therapeutic benefits in both hematopoietic and solid tumors. However, resistance to these drugs is a significant problem. Current MTAs bind to microtubules, and/or to their constituent tubulin heterodimers, and affect microtubule polymerization and dynamics. The PPARγinhibitor T0070907 can reduce tubulin levels in colorectal cancer cell lines and suppress tumor growth in a murine xenograft model. T0070907 does not alter microtubule polymerization in vitro, and does not appear to work by triggering modulation of tubulin RNA levels subsequent to decreased polymerization. This observation suggests the possible development of antimicrotubule drugs that work by a novel mechanism, and implies the presence of cancer therapeutic targets that have not yet been exploited. This review summarizes what is known about PPARγinhibitors and cancer cell death, with emphasis on the tubulin phenotype and PPAR-dependence, and identifies potential mechanisms of action.

scholarly journals Glycyrol Alone or in Combination with Gefitinib Is Effective against Gefitinib-Resistant HCC827GR Lung Cancer Cells

2021 ◽  
Vol 11 (22) ◽  
pp. 10526
Author(s):  
Shuang Zhao ◽  
Shangyun Lu ◽  
Lihong Fan ◽  
Hongbo Hu
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Lung Cancer Cells ◽  
Clinical Utilization ◽  
Murine Xenograft Model ◽  
Coumarin Compounds ◽  
Line Setting

Gefitinib has been clinically demonstrated to be effective in the first-line setting for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, acquired therapeutic resistance to gefitinib almost unavoidably develops, posing a major hurdle for its clinical utilization. Our previous study showed that glycyrol (GC), a representative of coumarin compounds isolated from the medicinal plant licorice, was effective against A549 lung cancer cells in both cell culture and a murine xenograft model. In this follow-up study, we evaluated the effect of glycyrol against gefitinib-resistant NSCLC and its ability to overcome the resistance using gefitinib-resistant HCC827GR cells. Results showed that glycyrol was effective against HCC827GR cells in both in vitro and in vivo. Moreover, glycyrol was able to significantly increase the sensitivity of HCC827GR cells to gefitinib, mechanistically associated with inactivating MET, which is a known important contributor to the resistance of HCC827GR cells to gefitinib. The findings of the present study suggest that glycyrol holds potential to be developed as a novel agent against gefitinib-resistant NSCLC.

scholarly journals Selenium Induces Pancreatic Cancer Cell Death Alone and in Combination with Gemcitabine

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 149
Author(s):  
David J. Wooten ◽  
Indu Sinha ◽  
Raghu Sinha
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Single Agent ◽  
Cancer Cell Lines ◽  
Chemotherapeutic Agents ◽  
Cancer Cell Death ◽  
Pancreatic Cancer Cells

Survival rate for pancreatic cancer remains poor and newer treatments are urgently required. Selenium, an essential trace element, offers protection against several cancer types and has not been explored much against pancreatic cancer specifically in combination with known chemotherapeutic agents. The present study was designed to investigate selenium and Gemcitabine at varying doses alone and in combination in established pancreatic cancer cell lines growing in 2D as well as 3D platforms. Comparison of multi-dimensional synergy of combinations’ (MuSyc) model and highest single agent (HSA) model provided quantitative insights into how much better the combination performed than either compound tested alone in a 2D versus 3D growth of pancreatic cancer cell lines. The outcomes of the study further showed promise in combining selenium and Gemcitabine when evaluated for apoptosis, proliferation, and ENT1 protein expression, specifically in BxPC-3 pancreatic cancer cells in vitro.

scholarly journals Membrane-bound TNF mediates microtubule-targeting chemotherapeutics-induced cancer cytolysis via juxtacrine inter-cancer-cell death signaling

2019 ◽  
Vol 27 (5) ◽  
pp. 1569-1587 ◽  
Author(s):  
Jing Zhang ◽  
Yu Yang ◽  
Shen’ao Zhou ◽  
Xueyan He ◽  
Xuan Cao ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Tumor Regression ◽  
Cell Types ◽  
Tight Contact ◽  
Cancer Cell Death ◽  
Microtubule Targeting Agents ◽  
Patient Responsiveness ◽  
Smac Mimetics

Abstract Microtubule-targeting agents (MTAs) are a class of most widely used chemotherapeutics and their mechanism of action has long been assumed to be mitotic arrest of rapidly dividing tumor cells. In contrast to such notion, here we show—in many cancer cell types—MTAs function by triggering membrane TNF (memTNF)-mediated cancer-cell-to-cancer-cell killing, which differs greatly from other non-MTA cell-cycle-arresting agents. The killing is through programmed cell death (PCD), either in way of necroptosis when RIP3 kinase is expressed, or of apoptosis in its absence. Mechanistically, MTAs induce memTNF transcription via the JNK-cJun signaling pathway. With respect to chemotherapy regimens, our results establish that memTNF-mediated killing is significantly augmented by IAP antagonists (Smac mimetics) in a broad spectrum of cancer types, and with their effects most prominently manifested in patient-derived xenograft (PDX) models in which cell–cell contacts are highly reminiscent of human tumors. Therefore, our finding indicates that memTNF can serve as a marker for patient responsiveness, and Smac mimetics will be effective adjuvants for MTA chemotherapeutics. The present study reframes our fundamental biochemical understanding of how MTAs take advantage of the natural tight contact of tumor cells and utilize memTNF-mediated death signaling to induce the entire tumor regression.

scholarly journals EVALUATION OF [11C]MPC-6827 AS A MICROTUBULE TARGETING PET RADIOTRACER IN CANCER CELL LINES

2019 ◽  
pp. 43-47
Author(s):  
J. S. DILEEP KUMAR ◽  
JAYA PRABHAKARAN ◽  
NARESH DAMUKA ◽  
JUSTIN W. HINES ◽  
STEVEN J. KRIDEL ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Specific Binding ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Microtubule Targeting Agents ◽  
Pc3 Cells

Objective: The objective of this study was to evaluate the uptake and specificity of [11C]MPC-6827, a MT targeted PET ligand in prostate, glioblastoma and breast cancer cells. Methods: [11C]MPC-6827 was synthesized by reacting corresponding desmethyl precursors with [11C]CH3I in a GE-FX2MeI/FX2M radiochemistry module. In vitro binding of [11C]MPC-6827 was performed in breast cancer MDA-MB-231, glioblastoma (GBM) patient-derived tumor (GBM-PDX), GBM U251 and prostate cancer 3 (PC3) cell lines at 37 °C in quadruplicate at 5, 15, 30, 60, and 90 minute incubation time. The nonspecific bindings were determined by incubation with unlabeled microtubule targeting agents MPC-6827, HD-800, colchicine, paclitaxel and docetaxel (5.0 mM). Results: [11C]MPC-6827 provided the highest binding in the breast cancer cell, MDA-MB-231, among all the cells studied, with 90% specific binding. [11C]MPC-6827 binds to glioblastoma PDX and U251 cells with ~50% and 40% specific binding, whereas, prostate cancer cell line, PC3 cells showed 40% specific binding. [11C]MPC-6827 also exhibits binding to the taxane and colchicine binding sites of MTs, in MDA-MB-231 cells. Conclusion: These data indicate that [11C]MPC-6827 can be a promising PET radiotracer for preclinical imaging of the brain and peripheral cancers.

scholarly journals Engineered Fragments of the PSMA-Specific 5D3 Antibody and Their Functional Characterization

2020 ◽  
Vol 21 (18) ◽  
pp. 6672
Author(s):  
Zora Novakova ◽  
Nikola Belousova ◽  
Catherine A. Foss ◽  
Barbora Havlinova ◽  
Marketa Gresova ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Xenograft Model ◽  
In Vitro Assays ◽  
Experimental Therapy ◽  
Single Chain ◽  
Single Chain Fv ◽  
Murine Xenograft Model ◽  
Single Target

Prostate-Specific Membrane Antigen (PSMA) is an established biomarker for the imaging and experimental therapy of prostate cancer (PCa), as it is strongly upregulated in high-grade primary, androgen-independent, and metastatic lesions. Here, we report on the development and functional characterization of recombinant single-chain Fv (scFv) and Fab fragments derived from the 5D3 PSMA-specific monoclonal antibody (mAb). These fragments were engineered, heterologously expressed in insect S2 cells, and purified to homogeneity with yields up to 20 mg/L. In vitro assays including ELISA, immunofluorescence and flow cytometry, revealed that the fragments retain the nanomolar affinity and single target specificity of the parent 5D3 antibody. Importantly, using a murine xenograft model of PCa, we verified the suitability of fluorescently labeled fragments for in vivo imaging of PSMA-positive tumors and compared their pharmacokinetics and tissue distribution to the parent mAb. Collectively, our data provide an experimental basis for the further development of 5D3 recombinant fragments for future clinical use.

scholarly journals Targeting lymphoma with precision using semisynthetic anti-idiotype peptibodies

2016 ◽  
Vol 113 (19) ◽  
pp. 5376-5381 ◽  
Author(s):  
James Torchia ◽  
Kipp Weiskopf ◽  
Ronald Levy
Keyword(s):  
B Cell ◽  
Xenograft Model ◽  
Variable Region ◽  
Cell Receptor ◽  
Specific Cell ◽  
Murine Xenograft Model ◽  
Surface Product ◽  
Human Lymphoma ◽  
Specific Cell Surface

B-cell lymphomas express a functionally active and truly tumor-specific cell-surface product, the variable region of the B-cell receptor (BCR), otherwise known as idiotype. The tumor idiotype differs, however, from patient to patient, making it a technical challenge to exploit for therapy. We have developed a method of targeting idiotype by using a semisynthetic personalized therapeutic that is more practical to produce on a patient-by-patient basis than monoclonal antibodies. In this method, a small peptide with affinity for a tumor idiotype is identified by screening a library, chemically synthesized, and then affixed to the amino terminus of a premade IgG Fc protein. We demonstrate that the resultant semisynthetic anti-idiotype peptibodies kill tumor cells in vitro with specificity, trigger tumor cell phagocytosis by macrophages, and efficiently clear human lymphoma in a murine xenograft model. This method could be used to target tumor with true precision on a personalized basis.

Sign in / Sign up

Export Citation Format

Share Document