bluuebunny/crossref_metadata_2025_split huggingface dataset:
Camptothecin- and etoposide-induced apoptosis in human leukemia cells is independent of cell death receptor-3 and -4 aggregation but accelerates tumor necrosis factor–related apoptosis-inducing ligand–mediated cell death
Authors: Bergeron Stephane , Beauchemin Myriam , Bertrand Richard 
Published: June 2022

Abstract
During camptothecin- and etoposide (VP-16)-induced apoptosis in HL-60 cells, the expression level of cell death receptor-3 (DR3), cell death receptor-4 (DR4), and FAS remained mostly unchanged, whereas the expression of silencers of death domain (SODD) and FLICE inhibitory proteins, inhibitors of the cell death receptor signaling pathways, decreased substantially. By indirect immunofluorescence and immunoperoxidase imaging and with gel filtration column chromatography, we observed rapid aggregation at the cell surface and the appearance of high molecular weight protein complexes primarily involving DR3, and DR3 and DR4 after camptothecin and VP-16 treatment, respectively. Both drugs failed to rapidly promote FAS aggregation in these cells. The high expression level of SODD or of dominant negative forms of FADD (FADD-DN) and DAP3 (DAP3-DN), or of NH 2-terminal deletion mutant of TRADD (TRADD-ND) achieved by transient transfection experiments, did not impair the kinetics of apoptosis after camptothecin and VP-16 treatment in HL-60 and U937 cells. Taken together, these observations suggested that camptothecin and VP-16 induced rapid aggregation of DR4 and DR3, but paradoxically, the importance of these events in signaling apoptosis is uncertain, because the kinetics of apoptosis were unaffected, even in the presence of a high expression level of SODD, FADD-DN, TRADD-ND, and DAP3-DN. However, camptothecin or VP-16 treatment in combination with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) substantially accelerated kinetics of apoptosis than treatment with camptothecin, VP-16, or TRAIL alone. In contrast, cotreatment of camptothecin or VP-16 with TWEAK or TL1A did not facilitate apoptosis in HL60 cells. These findings suggest that DR4 aggregation mediated by camptothecin or VP-16 could represent a mean that accelerates TRAIL-induced apoptosis.
Enhanced efficacy of therapy with antisense BCL-2 oligonucleotides plus anti-CD20 monoclonal antibody in scid mouse/human lymphoma xenografts
Authors: Smith Mitchell R. , Jin Fang , Joshi Indira 
Published: June 2022

Abstract
Monoclonal anti-CD20 antibody (rituximab) is active, but not curative, therapy for B-cell non-Hodgkin's lymphoma. BCL-2 is an antiapoptotic protein whose expression is dysregulated in most indolent B-cell malignancies. Antisense oligonucleotides (AS-ODNs) that down-regulate BCL-2 expression induce apoptosis and chemosensitize B-cell lymphoma cells. We hypothesized that BCL-2 down-regulation by AS-ODNs would sensitize cells to rituximab and improve therapeutic results. There is enhanced apoptosis and reduction in cell numbers when DoHH2 cells are treated in vitro with rituximab plus BCL-2 AS-ODNs, compared with either agent alone. There is little in vitro effect on WSU-FSCCL cells by rituximab, AS-ODNs that down-regulate BCL-2 by targeting the immunoglobulin portions of the BCL-2-immunoglobulin fusion molecule, or a combination of the two. The combination is more effective than either agent alone in clearing DoHH2 cells from ascites in scid mice. Combination therapy with AS-BCL-2-ODNs and rituximab significantly prolongs survival in both the DoHH2 and WSU-FSCCL models. With higher and repeated doses, this combination could be curative. We conclude that the combination of rituximab and antisense-mediated down-regulation of BCL-2 has enhanced activity against human lymphoma, prolongs survival, and could cure mice bearing human lymphoma. This merits investigation in clinical trials.
Cytochrome P450 enzymes: Novel options for cancer therapeutics
Authors: McFadyen Morag C. E. , Melvin William T. , Murray Graeme I. 
Published: June 2022

Abstract
The concept of overexpression of individual forms of cytochrome P450 enzymes in tumor cells is now becoming well recognized. Indeed, a growing body of research highlights the overexpression of P450s, particularly CYP1B1, in tumor cells as representing novel targets for anticancer therapy. The purpose of this review is to outline the novel therapeutic options and opportunities arising from both enhanced endogenous expression of cytochrome P450 in tumors and cytochrome P450-mediated gene therapy.
Proteasome-mediated degradation of cell division cycle 25C and cyclin-dependent kinase 1 in phenethyl isothiocyanate-induced G2-M-phase cell cycle arrest in PC-3 human prostate cancer cells
Authors: Xiao Dong , Johnson Candace S. , Trump Donald L. , Singh Shivendra V. 
Published: June 2022

Abstract
Phenethyl isothiocyanate (PEITC), a constituent of many cruciferous vegetables, offers significant protection against cancer in animals induced by a variety of carcinogens. The present study demonstrates that PEITC suppresses proliferation of PC-3 cells in a dose-dependent manner by causing G2-M-phase cell cycle arrest and apoptosis. Interestingly, phenyl isothiocyanate (PITC), which is a structural analogue of PEITC but lacks the -CH2 spacers that link the aromatic ring to the -N=C=S group, neither inhibited PC-3 cell viability nor caused cell cycle arrest or apoptosis. These results indicated that even a subtle change in isothiocyanate (ITC) structure could have a significant impact on its biological activity. The PEITC-induced cell cycle arrest was associated with a &gt;80% reduction in the protein levels of cyclin-dependent kinase 1 (Cdk1) and cell division cycle 25C (Cdc25C; 24 h after treatment with 10 μm PEITC), which led to an accumulation of Tyr15 phosphorylated (inactive) Cdk1. On the other hand, PITC treatment neither reduced protein levels of Cdk1 or Cdc25C nor affected Cdk1 phosphorylation. The PEITC-induced decline in Cdk1 and Cdc25C protein levels and cell cycle arrest were significantly blocked on pretreatment of PC-3 cells with proteasome inhibitor lactacystin. A 24 h exposure of PC-3 cells to 10 μm PEITC, but not PITC, resulted in about 56% and 44% decrease in the levels of antiapoptotic proteins Bcl-2 and Bcl-XL, respectively. However, ectopic expression of Bcl-2 failed to alter sensitivity of PC-3 cells to growth inhibition or apoptosis induction by PEITC. Treatment of cells with PEITC, but not PITC, also resulted in cleavage of procaspase-3, procaspase-9, and procaspase-8. Moreover, the PEITC-induced apoptosis was significantly attenuated in the presence of general caspase inhibitor and specific inhibitors of caspase-8 and caspase-9. In conclusion, our data indicate that PEITC-induced cell cycle arrest in PC-3 cells is likely due to proteasome-mediated degradation of Cdc25C and Cdk1, and ectopic expression of Bcl-2 fails to confer resistance to PEITC-induced apoptosis. Furthermore, the results of the present study point toward involvement of both caspase-8- and caspase-9-mediated pathways in apoptosis induction by PEITC.
The novel estrogen 17α-20Z-21-[(4-amino)phenyl]-19-norpregna-1,3,5(10),20-tetraene-3,17β-diol induces apoptosis in prostate cancer cell lines at nanomolar concentrations in vitro
Authors: Mobley James A. , L'Esperance James O. , Wu Mengchu , Friel Carolyn J. , Hanson Robert H. , Ho Shuk-Mei 
Published: June 2022

Abstract
Prostate cancer remains the number one cause of noncutaneous cancer, with 220,900 new cases predicted for the year 2003 alone. Of the more promising classes of compounds studied thus far for the treatment of prostate cancer, estrogens of various types have consistently exhibited antitumor activities both in vitro and in vivo. For this reason, we have synthesized and screened a library of unique 17α/11β modified 17β-estradiol (E2) analogues designed for estrogen receptor β (ER-β) specificity and a potential for cytotoxic activity directed toward prostate cancer cells. From this library, the novel compound 17α-20Z-21-[(4-amino)phenyl]-19-norpregna-1,3,5(10),20-tetraene-3,17β-diol (APVE2) was identified as the primary lead, found to induce a high level (&gt;90%) of cell death through an apoptotic mechanism, with an EC50 of 1.4, 2.7, and 16 nm in the LNCaP, PC3, and DU145 cell lines, respectively. APVE2 was found to bind to ER-β, albeit weakly, with an EC50 of 250 nm and a binding activity of 6.2% relative to E2, nearly two orders of magnitude less than the concentration required to induce apoptosis. APVE2 bound preferentially to ER-β by 7-fold over ER-α, and did not induce growth in the MCF-7 cell line, thus indicating that it is not a classical ER agonist. Furthermore, the cytotoxic actions of APVE2 were not reversed by co-treatment with a 50-fold excess E2. In summary, a novel 17 modified estrogen APVE2 was identified as a lead compound, capable of inducing apoptosis in three prostate cancer cell lines at low nanomolar concentrations, through a mechanism inconsistent with an ER-mediated mechanism.
Abstract A02: A case for re-examination of the contribution of nitro-PAHs to combustion-product carcinogenesis
Authors: Blackburn Gary 
Published: June 2022

Abstract
One of the most studied compounds in all of cancer research is the environmental carcinogen benzo[a]pyrene (BaP). There is little doubt that BaP and its PAH congeners are the principal carcinogens in products like coal tar pitch, a category 1 IARC carcinogen. However, their concentrations in other complex hydrocarbon mixtures, like uncracked petroleum oils, are too low to account for their overall carcinogenic potency (that is, discounting contributory factors like tumor promotion and cumulative mutagenic insult). Nonetheless, the potent carcinogenicity of BaP and other four- and five-ring PACs has made reducing the release of these compounds into the environment from their principal endogenous source, petroleum, a major goal of health and safety regulation. Similar efforts to minimize the levels of the same PAHs pyrosynthesized and released into the atmosphere by the combustion of carbon fuels, have, however, faced a far greater challenge, given the immensity of that release on a daily basis. Moreover, the regulatory focus on parent, largely unsubstituted, PAHs has led to a de-emphasis on other potential contributors to the carcinogenicity of complex hydrocarbon mixtures, which in the case of the combustion products studied here, include their nitro-PAH derivatives. There are valid reasons for this de-emphasis. But there are also grounds to believe that a re-examination of the nitro-PAH role in combustion product carcinogenesis is warranted. Among them are the demonstration by Rosenkranz et al. (Science 1980;209:1039-43) that one such compound, 1,8-dinitropyrene (DNP), induces over one million mutations per microgram in the Ames Test, and the Iwagawa et al. report (Carcinogenesis 1989;10:1285-90) that its isomer 1,6-DNP, when injected directly into the lungs of rats, exhibited three times the carcinogenic potency of BaP similarly introduced. The present report demonstrates that extracts of soot or ash from a variety of sources, including wood, liquified petroleum gas, and the burnt ends of cigarettes, contain an extremely potent Ames Test mutagen that, when fractionated by HPLC, coelutes with authentic DNP. These results would seem to be inconsistent with the known low activities in lung tissue of the nitroreductase required for DNP’s activation to its ultimate carcinogenic form. But one possible explanation for that apparent discrepancy is that populations of bacteria resident in the lung—many species of which are as nitroreductase-proficient as the Salmonella strains used in Ames testing—may be largely responsible for that activation.
Citation Format: Gary Blackburn. A case for re-examination of the contribution of nitro-PAHs to combustion-product carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A02.
Abstract A16: Environmental exposure to persistent organic pollutants (POPs) and primary colorectal cancer risk: A case-cohort study in a community-based perspective cohort
Authors: Kim Jinsun , Park Eun Young , Kim Byungmi , Lim Min Kyung , Oh Jin-Kyoung 
Published: June 2022

Abstract
Background: Recent studies suggest that the low-dose environmental exposure of persistent organic pollutants (POPs) may develop prostate cancer or breast cancer based on prospective cohort study design. This study investigates a relationship between environmental exposures to POPs and the development of colorectal cancer (CRC) in the general population.
Methods: We conducted a case-cohort study based on the Korean National Cancer Center Community Cohort, which included 16,304 adults who enrolled from 1993 to 2010 and followed by 2016 for the cancer incidence. We included 104 CRC cases and 235 adults in a subcohort and assessed their serum lipid-adjusted levels of 19 organochlorine pesticides (OCPs) and 32 polychlorinated biphenyls (PCBs). Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for determining the association between POPs and risk of CRC were estimated using logistic regression analyses, controlling for following covariates: age, sex, education, physical activity, meat consumption, vegetable/fruit consumption, drinking, smoking, obesity, pesticides use experience, and residential areas.
Results: Natural log-transformed cis-heptachlor epoxide and p,p’-DDD were significantly associated with increased risk of CRC [ORcis-heptachlor epoxide = 1.29, 95% CI: 1.03-1.62; ORp,p’-DDD = 1.63, 95% CI: 1.11-2.41] and increased ORs were also estimated for the highest versus lowest tertiles of these two metabolites [ORcis-heptachlor epoxide = 2.64, 95% CI: 1.24-5.6, p-trend = 0.021; ORp,p’-DDD = 3.51, 95% CI: 1.58-7.78, p-trend = 0.004]. Also, there was a significant association between natural log-transformed PCB 52 and risk of CRC (ORPCB 52 = 1.54, 95% CI: 1.06-2.24).
Conclusion: Higher exposure to POPs, such as cis-heptachlor epoxide, p,p’-DDD, and PCB 52, was associated with the elevated risk of CRC. Our findings from a community-based prospective cohort provide evidence on the relationship between environmental exposure of POPs and CRC in the general population.
Citation Format: Jinsun Kim, Eun Young Park, Byungmi Kim, Min Kyung Lim, Jin-Kyoung Oh. Environmental exposure to persistent organic pollutants (POPs) and primary colorectal cancer risk: A case-cohort study in a community-based perspective cohort [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A16.
Abstract A42: The search for new targets for mitigation of metal toxicity based on molecular pathways of action: A case study using cadmium and iron
Authors: Mudipalli Anuradha 
Published: June 2022

Abstract
Cadmium is a nonessential heavy metal, ubiquitous in nature with a long half-life in human beings. It is widely used in various industrial applications such as toy and jewelry making and is one of the key constituents of tobacco and cigarette smoke. Cadmium, both at occupational and environmental levels, has been implicated in the causation of cancerous and noncancerous health outcomes. In comparison, iron is an essential metal and is a constituent of hemoglobin and many vital enzymes and proteins and plays a pivotal role in human health. However, increased consumption of iron from fortified diets and iron supplements presents opportunities for exposure to supraphysiologic iron concentrations and toxicity. Additionally, hereditary iron disorders (thalassemia, hereditary hemochromatosis), other disease conditions such as cancer and kidney diseases, and certain environmental exposures (e.g., steel-welding fumes, asbestos, and air pollution) could also lead to iron toxicity with disturbed homeostasis mechanisms affecting intracellular and systemic regulation of iron. Chelation therapy has traditionally been used to mitigate the toxicity of metals. This talk will present the results of systematic reviews and analyses for both cadmium and iron toxicity and highlight the diverse molecular pathways by which these metals can elicit toxic effects. Using the examples of cadmium and iron, I will discuss some recent advances in our understanding of the molecular mechanisms of metal toxicity and how this information can be used to identify novel targets for toxicity mitigation. (The views expressed in this abstract are those of the author and do not necessarily reflect the views or policies of EPA.)
Citation Format: Anuradha Mudipalli. The search for new targets for mitigation of metal toxicity based on molecular pathways of action: A case study using cadmium and iron [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A42.
Abstract A47: PFOA and zeranol exposure during puberty affects the transcriptomic profile of the rat mammary gland
Authors: Dang Nhi M. , Su Yanrong , Santucci-Pereira Julia , Russo Jose 
Published: June 2022

Abstract
Background: Perfluorooctanoic acid (PFOA) and zeranol (Zer) are known as endocrine-disrupting chemicals (EDCs); however, their potential either alone or in combination of increasing the susceptibility to breast cancer is still not fully understood. Here, we hypothesize that pubertal exposure to these EDCs has an impact on the transcriptomic profile of the mammary glands, which explains the less differentiated phenotype and increased susceptibility to carcinogenesis when challenged with a chemical carcinogens like DMBA.
Methods: Female Sprague-Dawley rats at 21 days of age were assigned to four groups and received daily gavage for three weeks with PFOA and Zer alone or in combination. A control group received only sesame oil. At 50 days and 100 days of age (d50 and d100, respectively) the animals were euthanized and the mammary glands were collected, the RNA was extracted, and a RNA-seq library was constructed and sequenced.
Results: We detected differentially expressed genes (DEGs, absolute fold change &gt; 2 and FDR p&lt; 0.05) at d50 by PFOA 136 (106 up- and 30 downregulated), Zer 394 (370 up and 24 down), and PFOA+Zer 630 (244 up and 386 down); and at d100, PFOA 74 DEGs (23 up and 51 down), Zer 405 (11 up and 394 down), and PFOA+Zer 669 (98 up and 571 down). Zer and PFOA+Zer caused the remarkable number of genes with expression alteration at both of two endpoints. Gene ontology enrichment analyses revealed that zeranol affects immune response at d50 but is majorly associated with tissue development at d100, whereas PFOA affects cell development at d50 but is mainly related to morphogenesis at d100. Meanwhile, PFOA+Zer is associated with metabolic process at both of two endpoints. KEGG pathway analysis demonstrated that PFOA+Zer’s effects at both d50 and d100 were notably mediated through PI3K-Akt and PPAR signaling pathways.
Conclusion: A relevant and significant finding is that each compound induces a different transcriptomic profile and changes its biologic effects between day 50 and day 100 of age, and when both compounds are administered together the transcriptomic profile differs from that induced by each individual one. The major EDCs affected pathways are PI3K-Akt and PPAR signaling, indicating that the long-term damaging effect of the combination of EDCs explains the less differentiated phenotype and its higher susceptibility to develop mammary cancer when challenged with a chemical carcinogen. (This work was supported by the NIEHS/NCI grant U01ES026130 and NCI/NIH Cancer Center Support Grant P30-CA006927.)
Citation Format: Nhi M. Dang, Yanrong Su, Julia Santucci-Pereira, Jose Russo. PFOA and zeranol exposure during puberty affects the transcriptomic profile of the rat mammary gland [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A47.
Abstract A51: Mechanistic pathways for breast carcinogens can highlight early effects as predictive endpoints for chemical safety testing: Case studies for ionizing radiation and for in utero exposure to estrogens such as DES
Authors: Helm Jessica , Hindman Andrea , Rudel Ruthann A. 
Published: June 2022

Abstract
Knowledge about established breast carcinogens can support improved 21st-century toxicologic testing by identifying key mechanistic events. To clarify mechanisms, we developed adverse outcome pathways (AOPs) for two well-established breast carcinogens: ionizing radiation (IR) and the pharmaceutical hormone diethylstilbestrol (DES). The AOP for ionizing radiation includes these elements: IR increases production of reactive oxygen and nitrogen species (RONS), and directly and indirectly causes DNA damage. DNA damage leads to mutations and proliferation, leading to increased breast cancer. RONS also increases inflammation, contributing to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS, and separately increases breast cancer risk through increased proliferation of cells and increased tumor growth and invasion. Estrogen and progesterone also influence the risk of breast cancer from ionizing radiation, as does developmental stage. For in utero estrogens like DES, the AOP links gestational estrogen exposure to transcriptional activity that promotes altered signaling between the epithelial and stromal tissue compartments, leading to disrupted development, including altered tensional homeostasis and tissue architecture, inflammation, and altered cellular differentiation. These key events lead to several adverse outcomes at the tissue and organ level that increase susceptibility to breast cancer, including altered density, structure, and hormone sensitivity along with hyperplasia. Epigenetic alterations are a cellular-level outcome that propagates gestational estrogen exposure to later-life risk through cellular memory that directs ER-mediated gene expression and altered mammary development. Increased susceptibility to breast cancer follows from these adverse outcomes. Dose-response and developmental timing of exposure are discussed in both AOPs. These AOPs provide a framework for evaluating the potential for mechanistically similar stressors—e.g., genotoxicants/RONS-inducers may act like IR, or estrogenic chemicals in utero may act like DES—to affect breast cancer risk.
Citation Format: Jessica Helm, Andrea Hindman, Ruthann A. Rudel. Mechanistic pathways for breast carcinogens can highlight early effects as predictive endpoints for chemical safety testing: Case studies for ionizing radiation and for in utero exposure to estrogens such as DES [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A51.