Engineered Fully Human Single-Chain Monoclonal Antibodies to PIM2 Kinase

Proviral integration site of Moloney virus-2 (PIM2) is overexpressed in multiple human cancer cells and high level is related to poor prognosis; thus, PIM2 kinase is a rational target of anti-cancer therapeutics. Several chemical inhibitors targeting PIMs/PIM2 or their downstream signaling molecules have been developed for treatment of different cancers. However, their off-target toxicity is common in clinical trials, so they could not be advanced to official approval for clinical application. Here, we produced human single-chain antibody fragments (HuscFvs) to PIM2 by using phage display library, which was constructed in a way that a portion of phages in the library carried HuscFvs against human own proteins on their surface with the respective antibody genes in the phage genome. Bacterial derived-recombinant PIM2 (rPIM2) was used as an antigenic bait to fish out the rPIM2-bound phages from the library. Three E. coli clones transfected with the HuscFv genes derived from the rPIM2-bound phages expressed HuscFvs that bound also to native PIM2 from cancer cells. The HuscFvs presumptively interact with the PIM2 at the ATP binding pocket and kinase active loop. They were as effective as small chemical drug inhibitor (AZD1208, which is an ATP competitive inhibitor of all PIM isoforms for ex vivo use) in inhibiting PIM kinase activity. The HuscFvs should be engineered into a cell-penetrating format and tested further towards clinical application as a novel and safe pan-anti-cancer therapeutics.

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Targeting non-human coronaviruses to human cancer cells using a bispecific single-chain antibody

Gene Therapy ◽

10.1038/sj.gt.3302535 ◽

2005 ◽

Vol 12 (18) ◽

pp. 1394-1404 ◽

Cited By ~ 33

Author(s):

T Würdinger ◽

M H Verheije ◽

M Raaben ◽

B J Bosch ◽

C A M de Haan ◽

...

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Single Chain ◽

Single Chain Antibody ◽

Human Cancer Cells ◽

Human Coronaviruses

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Single-chain antibody-decorated Au nanocages@liposomal layer nanoprobes for targeted SERS imaging and remote-controlled photothermal therapy of melanoma cancer cells

Materials Science and Engineering C ◽

10.1016/j.msec.2021.112086 ◽

2021 ◽

Vol 124 ◽

pp. 112086

Author(s):

Ghazal Farahavar ◽

Samira Sadat Abolmaali ◽

Foroogh Nejatollahi ◽

Amin Safaie ◽

Sanaz Javanmardi ◽

...

Keyword(s):

Cancer Cells ◽

Photothermal Therapy ◽

Single Chain ◽

Single Chain Antibody ◽

Melanoma Cancer ◽

Sers Imaging

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Control of MYC-dependent apoptotic threshold by a co-amplified ubiquitin E3 ligase UBR5

10.1101/515247 ◽

2019 ◽

Author(s):

Xi Qiao ◽

Ying Liu ◽

Maria Llamazares Prada ◽

Abhishekh Gupta ◽

Alok Jaiswal ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Cancer Cells ◽

Ubiquitin Ligase ◽

Breast Cancer Cells ◽

Human Cancer ◽

Cancer Therapeutics ◽

Cancer Tissue ◽

Basal Type

AbstractMYC protein expression has to be tightly controlled to allow for maximal cell proliferation without inducing apoptosis. Here we discover UBR5 as a novel MYC ubiquitin ligase and demonstrate how it functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 effects on MYC protein stability are independent on N-terminal FBW7 degron of MYC. Endogenous UBR5 inhibition induces MYC protein expression and activates MYC target genes. Moreover, UBR5 governs MYC-dependent phenotypes in vivo in Drosophila. In cancer cells, UBR5-mediated MYC protein suppression diminishes cell killing activity of cancer therapeutics. Further, we demonstrate that UBR5 dominates MYC protein expression at the single-cell level in human basal-type breast cancer tissue. Myc and Ubr5 are co-amplified in MYC-driven human cancer types, and UBR5 controls MYC-mediated apoptotic threshold in co-amplified basal type breast cancer cells. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC protein expression in vivo. Clinically, expression of UBR5 may be important for protection of breast cancer cells from drug-induced, and MYC-dependent, apoptosis.

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Stress responses as master keys to epigenomic changes in transcriptome and metabolome for cancer etiology and therapeutics

Molecular and Cellular Biology ◽

10.1128/mcb.00483-21 ◽

2021 ◽

Author(s):

Atanu Mondal ◽

Apoorva Bhattacharya ◽

Vipin Singh ◽

Shruti Pandita ◽

Albino Bacolla ◽

...

Keyword(s):

Stress Response ◽

Cancer Cells ◽

Stress Responses ◽

Current Knowledge ◽

Cancer Therapeutics ◽

Molecular Architecture ◽

Cancer Etiology ◽

Treatment Scenario ◽

Anti Cancer ◽

Novel Therapeutic Strategies

From initiation through progression, cancer cells are subjected to a magnitude of endogenous and exogenous stresses, which aid in their neoplastic transformation. Exposure to these classes of stress induces imbalance in cellular homeostasis and, in response, cancer cells employ informative adaptive mechanisms to rebalance biochemical processes that facilitate survival and maintain their existence. Different kinds of stress stimuli trigger epigenetic alterations in cancer cells, which leads to changes in their transcriptome and metabolome, ultimately resulting in suppression of growth inhibition or induction of apoptosis. Whether cancer cells show a protective response to stress or succumb to cell death depends on the type of stress and duration of exposure. A thorough understanding of epigenetic and molecular architecture of cancer cell stress response pathways can unveil a plethora of information required to develop novel anti-cancer therapeutics. The present view highlights current knowledge about alterations in epigenome and transcriptome of cancer cells as a consequence of exposure to different physicochemical stressful stimuli such as reactive oxygen species (ROS), hypoxia, radiation, hyperthermia, genotoxic agents, and nutrient deprivation. Currently, an anti-cancer treatment scenario involving the imposition of stress on target cancer cells is gaining traction to augment or even replace conventional therapeutic regimens. Therefore, a comprehensive understanding of stress response pathways is crucial for devising and implementing novel therapeutic strategies.

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N-ω-chloroacetyl-l-ornithine, a new competitive inhibitor of ornithine decarboxylase, induces selective growth inhibition and cytotoxicity on human cancer cells versus normal cells

Journal of Enzyme Inhibition and Medicinal Chemistry ◽

10.3109/14756366.2014.926342 ◽

2014 ◽

Vol 30 (3) ◽

pp. 345-353 ◽

Cited By ~ 3

Author(s):

Miriam Marlene Medina-Enríquez ◽

Verónica Alcántara-Farfán ◽

Leopoldo Aguilar-Faisal ◽

José Guadalupe Trujillo-Ferrara ◽

Lorena Rodríguez-Páez ◽

...

Keyword(s):

Growth Inhibition ◽

Cancer Cells ◽

Ornithine Decarboxylase ◽

Human Cancer ◽

Competitive Inhibitor ◽

Selective Growth ◽

Normal Cells ◽

Human Cancer Cells

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Momordica charantiaExtract Induces Apoptosis in Human Cancer Cells through Caspase- and Mitochondria-Dependent Pathways

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/261971 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 19

Author(s):

Chia-Jung Li ◽

Shih-Fang Tsang ◽

Chun-Hao Tsai ◽

Hsin-Yi Tsai ◽

Jong-Ho Chyuan ◽

...

Keyword(s):

Cell Death ◽

Cytotoxic Activity ◽

Cancer Cells ◽

Dna Fragmentation ◽

Human Cancer ◽

Momordica Charantia ◽

Carcinoma Cells ◽

Human Cancer Cells ◽

Adenocarcinoma Cells ◽

Anti Cancer

Plants are an invaluable source of potential new anti-cancer drugs.Momordica charantiais one of these plants with both edible and medical value and reported to exhibit anticancer activity. To explore the potential effectiveness ofMomordica charantia, methanol extract ofMomordica charantia(MCME) was used to evaluate the cytotoxic activity on four human cancer cell lines, Hone-1 nasopharyngeal carcinoma cells, AGS gastric adenocarcinoma cells, HCT-116 colorectal carcinoma cells, and CL1-0 lung adenocarcinoma cells, in this study. MCME showed cytotoxic activity towards all cancer cells tested, with the approximate IC50ranging from 0.25 to 0.35 mg/mL at 24 h. MCME induced cell death was found to be time-dependent in these cells. Apoptosis was demonstrated by DAPI staining and DNA fragmentation analysis using agarose gel electrophoresis. MCME activated caspase-3 and enhanced the cleavage of downstream DFF45 and PARP, subsequently leading to DNA fragmentation and nuclear condensation. The apoptogenic protein, Bax, was increased, whereas Bcl-2 was decreased after treating for 24 h in all cancer cells, indicating the involvement of mitochondrial pathway in MCME-induced cell death. These findings indicate that MCME has cytotoxic effects on human cancer cells and exhibits promising anti-cancer activity by triggering apoptosis through the regulation of caspases and mitochondria.

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erbB-2 knockout employing an intracellular single-chain antibody (sFv) accomplishes specific toxicity in erbB-2-expressing lung cancer cells.

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/ajrcmb.15.3.8810638 ◽

1996 ◽

Vol 15 (3) ◽

pp. 348-354 ◽

Cited By ~ 15

Author(s):

J Grim ◽

J Deshane ◽

M Feng ◽

A Lieber ◽

M Kay ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Lung Cancer Cells ◽

Single Chain ◽

Single Chain Antibody

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Effects of a Novel Histone Deacetylase Inhibitor, PXD101, When Used as Monotherapy or in Combination with Bortezomib on Tumor Growth in Mouse Models of Human Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3483.3483 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3483-3483 ◽

Cited By ~ 1

Author(s):

Richard A. Campbell ◽

Eric Sanchez ◽

Haiming Chen ◽

Lauren Turker ◽

Olivia Trac ◽

...

Keyword(s):

Multiple Myeloma ◽

Cancer Cells ◽

Histone Deacetylase ◽

Mouse Models ◽

Optimal Schedule ◽

Cancer Therapeutics ◽

Mouse Serum ◽

Wide Range ◽

Anti Cancer ◽

Human Multiple Myeloma

Abstract Histone deacetylase (HDAC) inhibitors represent a new mechanistic class of anti-cancer therapeutics that inhibit HDAC enzymes and have been shown to have anti-proliferative effects in cancer cells (including drug resistance subtypes), induce apoptosis, inhibit angiogenesis, and sensitize cancer cells when combined with other available anti-cancer therapies. PXD101 is a novel investigational small molecule drug that selectively inhibits HDAC enzymes. In recent preclinical studies, PXD101 has been shown to have the potential to treat a wide range of solid and hematological malignancies either as a monotherapy or in combination with other active agents. In this study, we evaluated the activity of PXD101 on multiple myeloma samples when used as monotherapy or in combination with the proteasome inhibitor bortezomib. In vitro experiments indicated that PXD101 pretreatment (20 mM; 3h) sensitized RPMI-8226 human multiple myeloma cells to subsequent bortezomib exposure (5 nM; 72h). To examine PXD101 and bortezomib in vivo, two mouse models of human multiple myeloma were utilized (LAGλ-1 and LAGκ-1B). LAGλ-1 was generated from a patient resistant to melphalan therapy and LAGκ-1B from a patient who progressed on bortezomib treatment (Campbell et al, International Journal of Oncology 2006). SCID mice were implanted with LAGλ-1 or LAGκ-1B tumor fragments into the left superficial gluteal muscle. Tumors were allowed to grow for 14 days at which time human IgG levels were detectable in the mouse serum, and mice were randomly assigned into treatment groups. Groups consisted of Vehicle only, PXD101 alone (40 mg/kg), bortezomib alone (0.5 mg/kg), or PXD101 (40 mg/kg) + bortezomib (0.5 mg/kg). In one cohort, PXD101 and bortezomib were administered twice weekly (M, Th) and in another cohort PXD101 was administered 5 days a week (M-F) and bortezomib twice weekly (M, Th). When administered, PXD101 was given i.p twice daily and bortezomib once daily intravenously. The results of these animal experiments will provide preclinical information on the activity of PXD101 monotherapy and PXD101/bortezomib combination therapy on drug-resistant myeloma samples, and may help to define the optimal schedule for potential clinical evaluation of this drug combination.

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Synergistic Effects of Bifunctional Antibodies Against beta3 Integrin on Dissolution of Platelet Thrombus,

Blood ◽

10.1182/blood.v118.21.3350.3350 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3350-3350

Author(s):

Wei Zhang ◽

Suying Dang ◽

Thomas Wisniewski

Keyword(s):

Conflicts Of Interest ◽

Ex Vivo ◽

Synergistic Effects ◽

Fibrin Clot ◽

Clot Lysis ◽

Single Chain ◽

Single Chain Antibody ◽

Platelet Thrombus ◽

Platelet Aggregates

Abstract Abstract 3350 HIV-ITP patients have a unique Ab against platelet GPIIIa49-66 which induces oxidative platelet fragmentation in the absence of complement (Cell 106: 551, 2001; JCI 113: 973, 2004). Using a phage display single-chain antibody (scFv) library, we developed a novel human monoclonal scFv Ab against GPIIIa49-66 (named A11), which act similarly to the parental Ab (JBC 283: 3224, 2008). We then produced a bifunctional GPIIIa49-66 agent (named SLK), that targets newly deposited fibrin strands within and surrounding the platelet thrombus and has reduced effects on non-activated circulating platelets (Blood 116: 2336, 2010). In this study, we produced another bifunctional GPIIIa49-66 agent (named APAC), which homes to activated platelets. Like SLK, APAC destroys platelet aggregates ex vivo in an identical fashion with ∼85% destruction of platelet aggregates at 2 hrs. Platelet aggregate dissolution with a combination of SLK and APAC was ∼2 fold greater than either agent alone at 0.025 μM. Platelet-rich clot lysis experiments demonstrated the time required for 50% platelet-rich fibrin clot lysis (T50%) by APAC (95±6.1 min) was significantly longer than that by APAC+SLK (65±7.6 min) at a final concentration of 0.025 μM (APAC+SLK vs APAC, p<0.01). In comparison with APAC alone, the T50% of APAC+SLK was shortened by 1.56, 1.67 and 2.1 fold at the concentrations of 0.025, 0.5 and 0.1μM, respectively. Thus these low concentrations of a combination of both agents are likely to be more effective and less toxic when used therapeutically in vivo. Disclosures: No relevant conflicts of interest to declare.

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