bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells bothin vitroandin vivo
Authors: July Laura V. , Beraldi Eliana , So Alan , Fazli Ladan , Evans Kenneth , English John C. , Gleave Martin E. 
Published: June 2022

AbstractIntroduction: Lung cancer is highly lethal and resistant to most anticancer interventions. Treatment resistance is mediated, in part, by enhanced expression of cell survival proteins that help facilitate tumor progression. Clusterin is a stress-associated cytoprotective protein up-regulated by various apoptotic triggers in many cancers and confers treatment resistance when overexpressed. The objectives in this study were to evaluate clusterin expression levels in human lung cancer tissue, and to test effects of clusterin silencing using antisense oligonucleotides (ASOs) and short interfering double-stranded RNAs (siRNAs) on chemosensitivity in human lung cancer A549 cells. Methods: Clusterin immunostaining was evaluated in a tissue microarray of 149 spotted human lung cancers. The effects of clusterin ASO or siRNA treatment on clusterin expression and chemosensitivity to paclitaxel was examined in A549 cells in vitro while the ability of clusterin ASO to chemosensitize in vivo was evaluated in immunocompromised mice bearing A549 tumors. Results: More than 80% of human non-small cell lung cancers are immunoreactive for clusterin. Clusterin ASO or siRNA decreased clusterin mRNA expression in A549 cells &gt;75% in a dose-dependent, sequence-specific manner, and significantly enhanced chemosensitivity to paclitaxel in vitro. Characteristic apoptotic DNA laddering was observed after combined treatment with ASO plus paclitaxel, but not with either agent alone. In vivo administration of clusterin ASO, compared to mismatch control oligonucleotide, synergistically enhanced the effects of paclitaxel or gemcitibine to significantly delay A549 tumor growth. Conclusion: These findings identify clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced lung cancer.
Gonadotropin-releasing hormone receptor–targeted gene therapy of gynecologic cancers
Authors: Gründker Carsten , Huschmand Nia Abdohamid , Emons Günter 
Published: June 2022

Abstract
The majority of ovarian, endometrial, and breast cancers express gonadotropin-releasing hormone (GnRH) receptors. Apart from reproductive organs (ovaries, fallopian tubes, and uterus) that are normally removed during surgical therapy of ovarian or endometrial cancer, pituitary gonadotrophs also express GnRH receptors. The signal transduction pathway in tumor cells is basically different from the classic GnRH receptor signal transduction, which is known to operate in the pituitary gonadotrophs and can therefore be considered tumor specific. Other organs and hematopoetic stem cells do not express GnRH receptors. We have recently shown specific activation of nucleus factor κB in ovarian, endometrial, and breast cancers after treatment with GnRH agonists. Based on this tumor-specific signaling pathway and the distribution pattern of GnRH receptors, we have developed and successfully tested a gene therapy concept by using a GnRH analogue as an inducer for the transcription of a therapeutic gene in cell culture and in nude mice.
Phosphorothioate oligodeoxynucleotides and G3139 induce apoptosis in 518A2 melanoma cells
Authors: Lai Johnathan C. , Benimetskaya Luba , Khvorova Anastasia , Wu Sijian , Hua Emily , Miller Paul , Stein C.A. 
Published: June 2022

Abstract
In a previous study, we showed that G3139, an antisense phosphorothioate oligonucleotide that down-regulates the expression of Bcl-2 protein, did not cause chemosensitization of 518A2 melanoma cells. In this work, we show that G3139, and the 2-base mismatch, G4126, can initiate apoptosis in this and other melanoma cell lines as shown by increased cell surface Annexin V expression, typical nuclear phenotypic changes as assessed by 4′,6-diamidino-2-phenylindole staining, activation of caspase-3 (but not caspase-8) and Bid, appearance of DEVDase (but not IETDase) activity, and cleavage of poly(ADP-ribose)-polymerase 1. Depolarization of the mitochondrial membrane occurs as a relatively late event. All of these processes seem to be substantially, but perhaps not totally, Bcl-2 independent as shown by experiments employing an anti-Bcl-2 small interfering RNA, which as shown previously down-regulated Bcl-2 protein expression but did not produce apoptosis or chemosensitization in melanoma cells. In fact, these G3139-induced molecular events were not dramatically altered in cells that forcibly overexpressed high levels of Bcl-2 protein. Addition of irreversible caspase inhibitors (e.g., the pan-caspase inhibitor zVAD-fmk) to G3139-treated cells almost completely blocked cytotoxicity. Examination of the time course of the appearance of caspase-3 and cleaved poly(ADP-ribose)-polymerase 1 showed that this could be correlated with the release of cytochrome c from the mitochondria, an event that begins only ∼4 hours after the end of the oligonucleotide/LipofectAMINE 2000 5-hour transfection period. Thus, both G3139 and cytotoxic chemotherapy activate the intrinsic pathway of apoptosis in these cells, although Bcl-2 expression does not seem to contribute strongly to chemoresistance. These findings suggest that the attainment of G3139-induced chemosensitization in these cells will be difficult.
Silatecan DB-67 is a novel DNA topoisomerase I–targeted radiation sensitizer
Authors: Chen Allan Y. , Shih Shyh-Jen , Garriques Liza N. , Rothenberg Mace L. , Hsiao Michael , Curran Dennis P. 
Published: June 2022

Abstract
The silatecan 7-tert-butyldimethylsilyl-10-hydroxy-camptothecin (DB-67) represents a new generation of camptothecin derivatives that exhibits a potent in vitro DNA topoisomerase I (TOP1)–mediated DNA-damaging activity, improved blood stability, and holds significant promise for the treatment of human cancers. In this study, we characterize the role of TOP1 in mediating the radiosensitization activity of DB-67. As examined by clonogenic survival assay, DB-67 exhibited potent radiosensitization activity at a concentration 10-fold lower than camptothecin in the human glioma D54-MG and T-98G cells, which harbor wild-type and mutant p53, respectively. Analyzed by the single-hit multitarget model, DB-67 induced radiosensitization by obliterating the “shoulder” of the radiation survival curve in the D54-MG cells. The in vivo targeting of TOP1 by DB-67 was investigated by immunoblot analysis. In a dose-dependent manner, DB-67 specifically stimulates covalent linking of TOP1 to chromosomal DNA at concentrations 10-fold lower than camptothecin in the D54-MG cells. The potency of in vivo targeting of TOP1 by DB-67 correlates well with its cytotoxicity and radiosensitization activity. Furthermore, DB-67 exhibited substantially less cytotoxicity and radiosensitization activity in the TOP1 mutant Chinese hamster lung fibroblast DC3F/C-10 cells than in their parental DC3F cells. Together, our data show that DB-67 exhibits potent cytotoxicity and radiosensitization activity by targeting TOP1 in mammalian cells and has great potential for being developed to treat human cancers.
Retinoic acid-induced CD38 antigen as a target for immunotoxin-mediated killing of leukemia cells
Authors: Mehta Kapil , Ocanas Larry , Malavasi Fabio , Marks John W. , Rosenblum Michael G. 
Published: June 2022

Abstract
A major obstacle in the successful delivery of antibody-based therapeutics to tumor cells is the heterogeneity of target antigen expression. We reported previously that retinoic acid (RA) is a potent and selective inducer of the cell-surface antigen CD38 in myeloid leukemia cells. The purpose of this study was to determine whether the RA-induced CD38 antigen could be a target for an anti-CD38-based immunotoxin to induce selective killing of leukemia cells. The combination of RA and the anti-CD38 gelonin immunotoxin induced a synergistic killing of leukemia cells. Thus, coculture of myeloid leukemia cells and cell lines with as little as 1 nm RA in the presence of immunotoxin induced substantial killing (&gt;90%) of leukemia cell clones. More importantly, the blasts of myeloid leukemia patients, irrespective of their morphological and phenotypic features, also responded to the RA and immunotoxin combination when cultured ex vivo. A similar synergistic effect between RA and immunotoxin was observed against a multidrug-resistant variant subline of HL-60 cells. However, another variant of HL-60 cells, HL-60R, in which the retinoid receptor function has been abrogated by a trans-dominant-negative mutation, exhibited complete resistance to the immunotoxin-induced killing effect in the presence or absence of RA. Our results suggest that RA combined with anti-CD38-based therapeutic agent may offer exciting opportunities for the treatment of myeloid leukemias despite their multiplicity of genetic and clinical varieties.
The mitotic serine threonine kinase, Aurora-2, is a potential target for drug development in human pancreatic cancer
Authors: Rojanala Sangeeta , Han Haiyong , Muñoz Rubén M. , Browne Walden , Nagle Raymond , Von Hoff Daniel D. , Bearss David J. 
Published: June 2022

Abstract
Aurora-2 is a serine threonine kinase that associates with the centrosome. Overexpression or ectopic expression of Aurora-2 appears to alter centrosome number and function and has been implicated in a variety of human cancers. In this work, we demonstrate that Aurora-2 is both amplified and overexpressed in human pancreatic cancer cell lines, with a 2–5-fold increase in gene copy number and a 3–4-fold increase in protein levels compared with controls. Aurora-2 is also amplified and overexpressed in pancreatic cancers taken directly from patients. An immunohistochemistry of tissues taken directly from patients demonstrated an overexpression of Aurora-2 in 26 of 28 pancreatic cancers compared with 18 normal pancreas samples. Antisense nucleotides specifically targeted at Aurora-2 arrest the cell cycle in pancreatic cancer cells, indicating the potential of Aurora-2 as a therapeutic target in pancreatic cancer.
Selective inhibitors of MEK1/ERK44/42 and p38 mitogen-activated protein kinases potentiate apoptosis induction by sulindac sulfide in human colon carcinoma cells
Authors: Sun Yunjie , Sinicrope Frank A. 
Published: June 2022

Abstract
The nonsteroidal anti-inflammatory drug (NSAID) sulindac prevents experimental colon cancer and can regress precancerous polyps in humans. Sulindac sulfide inhibits cyclooxygenase (COX)-mediated prostaglandin synthesis and retards the growth of cultured colon cell lines primarily by inducing apoptosis. Given the known role of mitogen-activated protein kinase (MAPK) in signal transduction and the regulation of cell survival and death, we determined the effect of sulindac sulfide on MAPK activation, COX-2 expression, and apoptosis induction in HCA-7 human colon cancer cells. Sulindac sulfide treatment was associated with activation of ERKp44/42 and p38 MAPK in a dosage- and time-dependent manner, and also activated upstream MEK. Similar results were seen in HCT-15 cells and also with the selective COX-2 inhibitor NS398. ERKp44/42 and p38 activation were accompanied by an induction of COX-2 protein expression. Selective inhibitors of sulindac sulfide–induced ERKp44/42 (PD98059) and p38 MAPK (SB203580) activation also suppressed the induction of COX-2 by this NSAID. Furthermore, both MAPK inhibitors significantly augmented sulindac sulfide–induced apoptosis, as did suppression of constitutive COX-2 using antisense oligonucleotides. In conclusion, MEK/ERK and p38 MAPK activation mediate COX-2 induction by sulindac sulfide. Selective inhibitors of these MAPKs potentiate apoptosis induction by this NSAID, suggesting a novel strategy for the prevention or treatment of colorectal cancer.
The insulin-like growth factor-I (IGF-I) receptor kinase inhibitor NVP-ADW742, in combination with STI571, delineates a spectrum of dependence of small cell lung cancer on IGF-I and stem cell factor signaling
Authors: Warshamana-Greene G. Sakuntala , Litz Julie , Buchdunger Elisabeth , Hofmann Francesco , Garcı́a-Echeverrı́a Carlos , Krystal Geoffrey W. 
Published: June 2022

Abstract
Stem cell factor (SCF)/Kit and insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) autocrine loops play a prominent role in the growth of small cell lung cancer (SCLC). Previous data suggested that IGF-I protects cells from apoptosis induced by STI571, an efficient inhibitor of Kit signal transduction, by activating the critical phosphatidylinositol 3-kinase-Akt pathway. To determine if inhibition of IGF-IR signaling would be therapeutically relevant in SCLC, the activity of a novel kinase inhibitor of IGF-IR, NVP-ADW742 (Novartis Pharma AG, Basel, Switzerland), was characterized. Pretreatment of the H526 cell line with NVP-ADW742 inhibited IGF-IR signaling and growth with IC50 values between 0.1 and 0.4 μm. SCF-mediated Kit phosphorylation and Akt activation were inhibited with IC50 values in the 1–5 μm range. However, NVP-ADW742 affected neither hepatocyte growth factor-mediated Akt activation nor activity of constitutively active Akt. The therapeutic potential of NVP-ADW742 was assessed by determining its effect on growth of several SCLC cell lines in serum. These studies clearly delineated two populations of cell lines as determined by differential sensitivity to NVP-ADW742. One population, which lacks active SCF/Kit autocrine loops, was inhibited with IC50 values between 0.1 and 0.5 μm. A second population, which has active SCF/Kit autocrine loops, was inhibited with IC50 values in the 4–7 μm range. When these cell lines were treated with a combination of STI571 and NVP-ADW742, no advantage was seen in the former group, whereas, in the latter group, a clearly synergistic response to the combination was seen when growth, apoptosis, or Akt activation was assessed. These data demonstrate that NVP-ADW742 is a potent and selective IGF-IR kinase inhibitor that can efficiently inhibit the growth of cells that are highly dependent on IGF-I signaling. However, for optimal growth inhibition of SCLC cells with an active SCF/Kit autocrine loop, a combination of a Kit inhibitor (STI571) and an IGF-IR inhibitor (NVP-ADW742) appears to be necessary. These observations suggest that, in tumors in which critical signal transduction pathways can be activated by alternative receptors, optimal therapy may require inhibition of multiple receptors.
Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity
Authors: Mimnaugh Edward G. , Xu Wanping , Vos Michele , Yuan Xitong , Isaacs Jennifer S. , Bisht Kheem S. , Gius David , Neckers Len 
Published: June 2022

Abstract
The ansamycin antibiotic, geldanamycin, targets the hsp 90 protein chaperone and promotes ubiquitin-dependent proteasomal degradation of its numerous client proteins. Bortezomib is a specific and potent proteasome inhibitor. Both bortezomib and the geldanamycin analogue, 17-N-allylamino-17-demethoxy geldanamycin, are in separate clinical trials as new anticancer drugs. We hypothesized that destabilization of hsp 90 client proteins with geldanamycin, while blocking their degradation with bortezomib, would promote the accumulation of aggregated, ubiquitinated, and potentially cytotoxic proteins. Indeed, geldanamycin plus bortezomib inhibited MCF-7 tumor cell proliferation significantly more than either drug alone. Importantly, while control cells were unaffected, human papillomavirus E6 and E7 transformed fibroblasts were selectively sensitive to geldanamycin plus bortezomib. Geldanamycin alone slightly increased protein ubiquitination, but when geldanamycin was combined with bortezomib, protein ubiquitination was massively increased, beyond the amount stabilized by bortezomib alone. In geldanamycin plus bortezomib-treated cells, ubiquitinated proteins were mostly detergent insoluble, indicating that they were aggregated. Individually, both geldanamycin and bortezomib induced hsp 90, hsp 70, and GRP78 stress proteins, but the drug combination superinduced these chaperones and caused them to become detergent insoluble. Geldanamycin plus bortezomib also induced the formation of abundant, perinuclear vacuoles, which were neither lysosomes nor autophagosomes and did not contain engulfed cytosolic ubiquitin or hsp 70. Fluorescence marker experiments indicated that these vacuoles were endoplasmic reticulum derived and that their formation was prevented by cycloheximide, suggesting a role for protein synthesis in their genesis. These observations support a mechanism whereby the geldanamycin plus bortezomib combination simultaneously disrupts hsp 90 and proteasome function, promotes the accumulation of aggregated, ubiquitinated proteins, and results in enhanced antitumor activity.
Different DNA lesions trigger distinct cell death responses in HCT116 colon carcinoma cells
Authors: Bai Shaochun , Goodrich David W. 
Published: June 2022

Abstract
The pleiotrophic cellular response to DNA damage includes activation of cell cycle checkpoints, induction of DNA repair pathways, and initiation of programmed cell death among others. The fate of cells with damaged DNA depends on the coordination of these different responses. The clinical efficacy of genotoxic therapies is influenced by cell fate and thus by how the DNA damage response is coordinated. While a great deal has been learned about how different DNA lesions activate distinct cell cycle checkpoints and DNA repair pathways, less is known about whether the type of DNA lesion influences the qualitative and quantitative nature of the cell death response. To address this question, HCT116 colon carcinoma cells have been treated with equally cytotoxic doses of the antitumor DNA alkylating agents adozelesin or bizelesin or the DNA strand scission agent C-1027. The relative contribution of cell cycle arrest and cell death to measured cytotoxicity varied among the three drugs. Apoptotic cell death accounts for most C-1027 cytotoxicity while cell cycle arrest and cell death both contribute to the cytotoxicity of the alkylating agents. Each of the drugs induces a distinct but overlapping pattern of caspase activation. In addition, the cell death response to these drugs is differentially dependent on p53 and p21. These observations suggest that the type of DNA lesion influences not only the relative extent of apoptotic cell death at a given cytotoxic dose but also the qualitative nature of that response.
Identification of human polo-like kinase 1 as a potential therapeutic target in pancreatic cancer
Authors: Gray Phillip J. , Bearss David J. , Han Haiyong , Nagle Raymond , Tsao Ming-Sound , Dean Nicholas , Von Hoff Daniel D. 
Published: June 2022

Abstract
Pancreas cancer is the fourth leading cause of cancer-related death in adults in the United States. New molecular targets for diagnosis and therapy of this disease are desperately needed. In this study, we report on the mitotic serine-threonine kinase polo-like kinase 1 (Plk1) in pancreatic cancer. Plk1 mRNA was found to be overexpressed in 9 of 10 tested pancreatic cancer cell lines and in 4 of 4 tested human tumors. Immunohistochemical staining of a pancreatic tissue microarray showed that 26 of the 35 tumors taken directly from patients overexpressed Plk1. We also examined the effects of depleting Plk1 in pancreatic cancer cells by the use of antisense oligonucleotides. Antisense-treated pancreatic cancer cells showed cell cycle arrest in G2-M as well as a drastic reduction in proliferation rates. These data suggest that Plk1 is a potential therapeutic target in devising a treatment for patients with pancreatic cancer.
Interstitial gene delivery in human xenograft prostate tumors using titanium metal seeds
Authors: Jung Mira , Zhang Yin , Dimtchev Alexandre , Subramanian Manny R. , Suthanthiran Krishman , Dritschilo Anatoly 
Published: June 2022

Abstract
Gene therapy is a promising approach for the treatment of cancers. Strategies for gene vector delivery include systemic and local-regional approaches. Intratumoral delivery of vectors has generally employed direct injections into single or multiple locations throughout the tumor volume. However, this approach leads to nonuniform distributions of reagents within tumors and becomes cumbersome as the required number of injections is increased. We have investigated the effectiveness of an interstitial plasmid gene delivery based on using tiny metallic seeds (GeneSeeds) analogous to technology used for brachytherapy. Feasibility for interstitial use of GeneSeeds was demonstrated expressing reporter plasmids (green fluorescence protein or β-galactosidase) in human xenograft prostate tumors. Immunohistochemical analysis confirmed effective interstitial delivery, vector expression, and distributions of reporter genes within tumors. Applicability of GeneSeeds for delivery of radiosensitizing cytokines was examined by generating a cytokine [tumor necrosis factor-α (TNF-α)] expressing vector under the cytomegaloviral promoter and interstitially implanting GeneSeeds with this vector into prostate cancer tumors. TNF-α protein expression was observed around the ends of seeds and decreasing in an exponential gradient as a function of distance. The expression of TNF-α resulted in tumor growth delay of a human prostate cancer xenograft. These results demonstrate the feasibility of applying interstitial delivery of gene expressing vectors for the treatment of human cancers.
X-linked inhibitor of apoptosis protein inhibition induces apoptosis and enhances chemotherapy sensitivity in human prostate cancer cells
Authors: Amantana Adams , London Carla A. , Iversen Patrick L. , Devi Gayathri R. 
Published: June 2022

Abstract
Androgen-insensitive prostate cancer cells are highly resistant to several chemotherapeutic drugs and are characterized by the appearance of apoptosis-resistant cells. In this study, we identified the critical role of X-linked inhibitor of apoptosis protein (XIAP), a potent antiapoptotic factor, in conferring chemotherapy resistance in an androgen-insensitive DU145 human prostate cancer cell line. Results reveal that DU145 cells were highly resistant to cisplatin, but this resistance was overridden when the cells were treated for a prolonged time (&gt;96 hours) with cisplatin (IC50 = 27.5 to 35.5 μmol/L). A decrease in levels of XIAP and Akt/phospho-Akt and an increase in caspase-3 activity were identified to be key factors in cisplatin sensitivity (40% to 55% decrease in cell viability) at later time points. In contrast, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) treatment caused a 40% to 50% decrease in cell viability within 6 hours (IC50 = 135 to 145 ng/mL). However, increasing concentrations or prolonged treatment with TRAIL did not change drug potency. A significant increase in caspase-3 activity was observed with TRAIL treatment with no apparent change in XIAP levels. Specific inhibition of XIAP expression using an antisense XIAP phosphorodiamidate morpholino oligomer induced apoptosis and increased caspase-3 activity. Combination of cisplatin with XIAP antisense potentiated cisplatin sensitivity by decreasing the IC50 from &gt;200 μmol/L with cisplatin alone to 9 to 20 μmol/L and decreasing incubation time required for activity from 96 to 24 hours. Similarly, TRAIL in combination with XIAP antisense phosphorodiamidate morpholino oligomer enhanced TRAIL potency by 12- to 13-fold. In conclusion, abrogation of XIAP expression is essential for therapeutic apoptosis and enhanced chemotherapy sensitization in androgen-refractory prostate cancer cells.