bluuebunny/crossref_metadata_2025_split huggingface dataset:
Marine natural products as anticancer drugs
Authors: Simmons T. Luke , Andrianasolo Eric , McPhail Kerry , Flatt Patricia , Gerwick William H. 
Published: June 2022

Abstract
The chemical and biological diversity of the marine environment is immeasurable and therefore is an extraordinary resource for the discovery of new anticancer drugs. Recent technological and methodologic advances in structure elucidation, organic synthesis, and biological assay have resulted in the isolation and clinical evaluation of various novel anticancer agents. These compounds range in structural class from simple linear peptides, such as dolastatin 10, to complex macrocyclic polyethers, such as halichondrin B; equally as diverse are the molecular modes of action by which these molecules impart their biological activity. This review highlights several marine natural products and their synthetic derivatives that are currently undergoing clinical evaluation as anticancer drugs.
TNP-470 promotes initial vascular sprouting in xenograft tumors
Authors: Huang Jianzhong , Frischer Jason S. , New Tamara , Kim Eugene S. , Serur Anna , Lee Alice , Kadenhe-Chiwishe Angela , Pollyea Daniel A. , Yokoi Akiko , Holash Jocelyn , Yancopoulos George D. , Kandel Jessica J. , Yamashiro Darrell J. 
Published: June 2022

Abstract
TNP-470 (AGM-1470), an analogue of fumagillin, was one of the first molecules proposed to have antiangiogenic properties. This concept was based on its ability to inhibit both endothelial proliferation in vitro and tumor growth in vivo in a number of xenograft models. Yet, subsequent investigations indicated that the biochemical activities associated with TNP-470 are not selective for endothelial cells. Moreover, recent evidence suggests that this agent inhibits tumor growth in vivo, but without a corresponding decrease in angiogenesis. Therefore, we performed a detailed comparison of TNP-470 to a validated antiangiogenic agent, a VEGF inhibitor termed VEGF-Trap, using a xenograft model of Wilms tumor. Treatment with TNP-470 for 5 weeks significantly suppressed xenograft growth (83%). Surprisingly, this inhibition was not associated with a decrease in angiogenesis, but instead with an increase in tiny neovessels. To determine whether this was a direct effect of TNP-470 on tumor vessels, we examined its effect in a short-term assay using large tumors with established vasculature. In contrast to treatment with VEGF-Trap, which led to rapid vessel regression and tumor hypoxia, tumors exposed to TNP-470 for 1 day displayed increased capillary sprouting, with significantly increased microvessel density, vessel length, and branch points. TNP-470 did not induce tumor hypoxia as demonstrated by minimal pimonidazole staining and VEGF expression. TNP-470 did, however, cause a marked increase in apoptosis of tumor cells. Our results indicate that the antitumor effects of TNP-470 cannot be attributed to prevention of neoangiogenesis, but instead to its direct action on tumor cells.
Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation
Authors: Ono Mayumi , Hirata Akira , Kometani Takuro , Miyagawa Miho , Ueda Shu-ichi , Kinoshita Hisafumi , Fujii Teruhiko , Kuwano Michihiko 
Published: June 2022

Abstract
Gefitinib (Iressa, ZD1839), a quinazoline tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR), is approved for patients with advanced non-small cell lung cancer (NSCLC) in several countries including Japan. However, the mechanism of drug sensitivity to gefitinib is not fully understood. In this study, we examined the molecular basis of sensitivity to gefitinib using nine human lung cancer cell lines derived from NSCLC. PC9 was the most sensitive to gefitinib of the nine NSCLC cell lines when assayed either by colony formation or MTS assays. The various cell lines expressed different levels of EGFR, HER2, HER3, and HER4, but there was no correlation between levels of EGFR and/or HER2 expression and drug sensitivity. Phosphorylation of EGFR, protein kinase B/AKT (Akt), and extracellular signal-regulated kinase (ERK) 1/2 was inhibited by much lower concentration of gefitinib in PC9 cells than in the other eight cell lines under exponential growing conditions. About 80% of cell surface EGFR in PC-9 was internalized within 10 min, whereas only about 30–50% of the cell surface EGFR was internalized in more drug-resistant cell lines in 15–60 min. The present study is the first to demonstrate that sensitivity to growth inhibition by gefitinib in NSCLC cell lines under basal growth condition is associated with dependence on Akt and ERK1/2 activation in response to EGFR signaling for survival and proliferation and also that drug sensitivity may be related to the extent of EGF-induced down-regulation of cell surface EGFR.
Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression
Authors: Swenson Stephen , Costa Fritz , Minea Radu , Sherwin Russell P. , Ernst William , Fujii Gary , Yang Dongyun , Markland Francis S. 
Published: June 2022

Abstract
Despite significant research in this area, metastatic breast cancer remains a disease with a poor prognosis. Until an effective therapy is developed, it is imperative that new treatment modalities be investigated. In this report, we describe an effective method for delivery of a novel snake venom disintegrin, contortrostatin (CN), in an orthotopic, xenograft model of human mammary cancer in immunodeficient mice. CN (Mr 13,500) is a homodimeric disintegrin isolated from venom of the Southern Copperhead snake. The homodimer possesses two Arg-Gly-Asp sites, which modulate its interaction with integrins on tumor cells and angiogenic vascular endothelial cells. Although our laboratory has previously described the antitumor activity of CN in a mouse model of human mammary cancer, the method of delivery, daily intratumor injection, was not translatable to clinical application. We now describe a clinically relevant method of administering CN, liposomal delivery (LCN). A unique liposomal system has been designed for i.v. administration of a biologically active protein with full retention of biological activity. Pharmacokinetics, biodistribution, platelet reactivity, and immunogenicity of LCN were determined and compared with similar characteristics of native, unencapsulated CN. There are several advantages to liposomal delivery of CN: (1) LCN has a significantly prolonged circulatory half-life compared with native CN; (2) LCN is passively accumulated in the tumor; (3) LCN has no platelet reactivity; and (4) LCN is not recognized by the immune system. Finally, antiangiogenic activity is an important component of CN's mechanism of antitumor action. We have demonstrated that i.v. delivery of LCN leads to potent antiangiogenic activity in the orthotopic, xenograft human mammary tumor model.
Nitric oxide prodrugs and metallochemotherapeutics: JS-K and CB-3-100 enhance arsenic and cisplatin cytolethality by increasing cellular accumulation
Authors: Liu Jie , Li Chengxiu , Qu Wei , Leslie Elaine , Bonifant Challice L. , Buzard Gregory S. , Saavedra Joseph E. , Keefer Larry K. , Waalkes Michael P. 
Published: June 2022

AbstractDevelopment of chemotherapeutic resistance is a major cause of pharmacologic failure in cancer treatment. One mechanism of resistance in tumor cells is the overexpression of glutathione S-transferases (GSTs) that serve two distinct roles in the development of drug resistance via the formation of glutathione conjugates with drugs for their cellular efflux, and the inhibition of the mitogen-activated protein kinase pathway. To target GST-based resistance to chemotherapeutics, a series of nitric oxide (NO)-releasing diazeniumdiolates was synthesized and shown to release NO on reaction with GST and/or glutathione. Two diazeniumdiolates, JS-K [O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] and CB-3-100 [O2-(2,4-dinitrophenyl) 1-[4-(N,N-diethylcarboxamido)piperazin-1-yl]diazen-1-ium-1,2-diolate], were studied on their ability in reversing arsenic and cisplatin resistance in a rat liver cell line that is tumorigenic and shows acquired tolerance to arsenic and cisplatin, with overexpression of GSTs. The enhanced cytolethality produced by the NO donors was accompanied by increased accumulation of arsenic and platinum within cells and by enhanced activation of mitogen-activated protein kinase members c-jun-NH-kinase and extracellular signal-regulated kinase. Our data indicate that JS-K and CB-3-100 are promising lead compounds for the possible development of a novel class of adjuvant chemotherapeutic agents potentially capable of reversing arsenic and cisplatin resistance in certain tumor cells.
Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis
Authors: Jazirehi Ali R. , Bonavida Benjamin 
Published: June 2022

Abstract
Resveratrol (trans-3,4,5-trihydroxystilbene) has received attention for its potential chemopreventive and antitumor effects in experimental systems. Recent evidence suggests that paclitaxel, alone or in combination with other drugs, can be effectively used in the treatment of non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). This study investigated whether resveratrol can sensitize NHL and MM cell lines to paclitaxel-mediated apoptosis and to delineate the underlying molecular mechanism of sensitization. Both resveratrol and paclitaxel negatively modulated tumor cell growth by arresting the cells at the G2-M phase of the cell cycle. Low concentrations of resveratrol exerted a sensitizing effect on drug-refractory NHL and MM cells to apoptosis induced by paclitaxel. Resveratrol selectively down-regulated the expression of antiapoptotic proteins Bcl-xL and myeloid cell differentiation factor-1 (Mcl-1) and up-regulated the expression of proapoptotic proteins Bax and apoptosis protease activating factor-1 (Apaf-1). Paclitaxel down-regulated the expression of Bcl-xL, Mcl-1, and cellular inhibitor of apoptosis protein-1 antiapoptotic proteins and up-regulated Bid and Apaf-1. Combination treatment resulted in apoptosis through the formation of tBid, mitochondrial membrane depolarization, cytosolic release of cytochrome c and Smac/DIABLO, activation of the caspase cascade, and cleavage of poly(adenosine diphosphate-ribose) polymerase. Combination of resveratrol with paclitaxel had minimal cytotoxicity against quiescent and mitogenically stimulated human peripheral blood mononuclear cells. Inhibition of Bcl-xL expression by resveratrol was critical for chemosensitization and its functional impairment mimics resveratrol-mediated sensitization to paclitaxel-induced apoptosis. Inhibition of Bcl-xL expression by resveratrol was due to the inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and diminished activator protein-1-dependent Bcl-xL expression. The findings by resveratrol were corroborated with inhibitors of the ERK1/2 pathway. This study demonstrates that in resistant NHL and MM cell lines resveratrol and paclitaxel selectively modify the expression of regulatory proteins in the apoptotic signaling pathway and the combination, via functional complementation, results in synergistic apoptotic activity.
Maximal apoptosis of renal cell carcinoma by the proteasome inhibitor bortezomib is nuclear factor-κB dependent
Authors: An Jiabin , Sun Yiping , Fisher Myrna , Rettig Matthew B. 
Published: June 2022

Abstract
Advanced renal cell carcinoma (RCC) is resistant to cytotoxic chemotherapy, and immunotherapy has modest activity. Proteasome inhibitors represent a novel class of anticancer agents that have activity across a wide spectrum of tumor types. We investigated the efficacy of the proteasome inhibitor bortezomib (VELCADE, formerly known as PS-341) in RCC and found that bortezomib potently induces apoptosis of RCC cell lines. Blockade of the nuclear factor-κB (NF-κB) pathway is considered a crucial effect in bortezomib-induced apoptosis, but the dependence on NF-κB inhibition for bortezomib-mediated death has not been formally demonstrated. Thus, we also studied the contribution of NF-κB inhibition as a mechanism of bortezomib-induced apoptosis in RCC cells, which display constitutive NF-κB activation. Ectopic expression of the NF-κB family members, p65 (Rel A) and p50 (NF-κB1), markedly reduced bortezomib-induced apoptosis. However, when we used selective genetic and chemical inhibitors of NF-κB, we found that NF-κB blockade was not sufficient to induce apoptosis of RCC cells. Thus, we conclude that maximal bortezomib-induced apoptosis is dependent on its NF-κB inhibitory effect, but NF-κB-independent effects also play a critical role in the induction of apoptosis by bortezomib. This represents the first report to formally demonstrate that bortezomib-induced NF-κB blockade is required to achieve the maximum degree of apoptosis by this drug.
Selenite-induced p53 Ser-15 phosphorylation and caspase-mediated apoptosis in LNCaP human prostate cancer cells
Authors: Jiang Cheng , Hu Hongbo , Malewicz Barbara , Wang Zaisen , Lü Junxuan 
Published: June 2022

Abstract
The issue of p53 requirement for the caspase-mediated apoptosis induced by selenium in a cancer chemoprevention or chemotherapy context has not been critically addressed. We and others have shown that selenite induces apoptotic DNA laddering in the p53-mutant DU145 prostate cancer cells and the p53-null HL60 leukemia cells without the cleavage of poly(ADP-ribose) polymerase (PARP; i.e., caspase-independent apoptosis), whereas selenium compounds leading to the formation of methylselenol induce caspase-mediated apoptosis in these cells. Because selenite induces DNA single strand breaks, and because certain types of DNA damage activate p53, we investigated whether the human LNCaP prostate cancer cells, which contain a wild-type p53, execute selenite-induced apoptosis through caspase pathways. The results showed that exposure of LNCaP cells for 24 hours to lower micromolar concentrations of selenite led to DNA laddering, and to the cleavage of PARP and several pro-caspases. In contrast to this apoptosis sensitivity, LNCaP cells were rather resistant to similar concentrations of the methylselenol precursor methylseleninic acid. Selenite treatment led to a significant increase in p53 phosphorylation on Ser-15 (Ser15P). Time course experiments showed that p53 Ser15P occurred several hours before caspase activation and PARP cleavage. The general caspase inhibitor zVADfmk completely blocked PARP cleavage, and significantly decreased DNA laddering, but did not affect p53 Ser15P. An inhibitor for caspase-8 was equally as protective as that for caspase-9 against the selenite-induced apoptosis. Attenuating p53 by a chemical inhibitor pifithrin-α decreased the selenite-induced p53 Ser15P and led to concordant reductions of PARP cleavage and apoptosis. In summary, selenite-induced p53 Ser15P appeared to be important for activating the caspase-mediated apoptosis involving both the caspase-8 and the caspase-9 pathways in the LNCaP cells.
Polyomavirus middle T–induced mammary intraepithelial neoplasia outgrowths: Single origin, divergent evolution, and multiple outcomes
Authors: Maglione Jeannie E. , McGoldrick Erik T. , Young Lawrence J.T. , Namba Ruria , Gregg Jeffrey P. , Liu Lin , Moghanaki Drew , Ellies Lesley G. , Borowsky Alexander D. , Cardiff Robert D. , MacLeod Carol L. 
Published: June 2022

Abstract
The development of models to investigate the pathobiology of premalignant breast lesions is a critical prerequisite for development of breast cancer prevention and early intervention strategies. Using tissue transplantation techniques, we modified the widely used polyomavirus middle T (PyV-mT) transgenic mouse model of breast cancer to study the premalignant stages of tumorigenesis. Premalignant atypical lesions were isolated from PyV-mT transgenic mice and used to generate two sets of three mammary intraepithelial neoplasia (MIN) outgrowth lines. Investigation of these six unique lines, each of which fulfills the criteria for MIN, has provided new information regarding the biology of PyV-mT-induced neoplasia. Although expression of the PyV-mT transgene was the primary initiating event for all lines, they exhibited different tumor latencies, metastatic potentials, and morphologies. Six distinguishable morphologic patterns of differentiation were identified within the premalignant outgrowths that are likely to represent several tumorigenic pathways. Further, several tumor phenotypes developed from each line and the tumors developing from the six lines had different metastatic potentials. These observations are consistent with the hypothesis that distinct pathways of PyV-mT-initiated neoplastic progression lead to different outcomes with respect to latency and metastasis. The MIN outgrowth lines share several characteristics with precursors of human breast cancer including the observation that gene expression profiles of tumors are more similar to those of the MIN outgrowth line outgrowth from which they developed than to other tumors. These lines provide an opportunity to study the full range of events occurring secondary to PyV-mT expression in the mammary gland.
Monounsaturated Fatty Acids: Key Regulators of Cell Viability and Intracellular Signaling in Cancer
Authors: Scott Julia S. , Nassar Zeyad D. , Swinnen Johannes V. , Butler Lisa M. 
Published: June 2022

Abstract
Cancer cells feature increased macromolecular biosynthesis to support the formation of new organelles and membranes for cell division. In particular, lipids are key macromolecules that comprise cellular membrane components, substrates for energy generation and mediators of inter- and intracellular signaling. The emergence of more sensitive and accurate technology for profiling the “lipidome” of cancer cells has led to unprecedented leaps in understanding the complexity of cancer metabolism, but also highlighted promising therapeutic vulnerabilities. Notably, fatty acids, as lipid building blocks, are critical players in all stages of cancer development and progression and the importance of fatty acid desaturation and its impact on cancer cell biology has been well established. Recent years have seen the reports of new mechanistic insights into the role of monounsaturated fatty acids (MUFA) in cancer, as regulators of cell death and lipid-related cellular signaling. This commentary aims to highlight these diverse roles of MUFAs in cancer cells which may yield new directions for therapeutic interventions involving these important fatty acids.
Abstract A30: Single-cell RNA-sequencing analysis of estrogen and the endocrine-disrupting chemical induced mouse mammary gland reorganization after surgical menopause
Authors: Chen Shiuan , Kanaya Noriko , Chang Gregory , Wu Xiwei , Saeki Kohei , Bernal Lauren , Dynold Timothy , Neuhausen Susan L. 
Published: June 2022

Abstract
Menopause is considered a critical window of susceptibility (WOS) for its sensitivity to endocrine-disrupting chemicals due to decline of endogenous estrogen. Using a surgical menopausal (ovariectomized) mouse model, we assessed how mammary gland tissue was affected by both 17β-estradiol (E2) and polybrominated diphenyl ethers (PBDEs). These endocrine-disrupting chemicals have been used as flame retardants in common household products since the 1970s and are vastly detected in human serum. During physiologically relevant exposure to E2, PBDEs enhanced E2-mediated regrowth of mammary glands with terminal end budlike structures. To better elucidate the effects of E2 and PBDEs, single-cell RNA sequencing (scRNAseq) analysis was performed. In a definitive manner, E2 was found to induce Pgr expression in both Esr1+ and Esr1- cells. We identified PBDE-impacted cell populations, Esr1+/Pgr+ and Esr1-/Pgr+ cells, in both mature luminal epithelial and progenitor cells, as well as the mammary gland population of M2 macrophages. Significantly, scRNAseq data show gene expression differences among cells with differential expression of Esr1 and Pgr. The results help clarify how exposure to both E2 and endocrine-disrupting chemicals like PBDEs after menopause impacts mammary gland structure. Ultimately, the findings advance understanding of how such exposure can increase the risk of developing breast cancer through the expansion of estrogen-responsive cells. (Supported by NIH U01ES026137.)
Citation Format: Shiuan Chen, Noriko Kanaya, Gregory Chang, Xiwei Wu, Kohei Saeki, Lauren Bernal, Timothy Dynold, Susan L. Neuhausen. Single-cell RNA-sequencing analysis of estrogen and the endocrine-disrupting chemical induced mouse mammary gland reorganization after surgical menopause [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 A30.
Abstract A48: Perinatal DDT exposure shortens latency of mouse mammary tumorigenesis
Authors: Ishikawa Tomoko , Tong Jason , Borowsky Alexander , Cardiff Robert , La Merrill Michele 
Published: June 2022

Abstract
The contribution of exposure to the persistent, lipophilic pesticide dichlorodiphenyltrichloroethane (DDT) to breast cancer risk is controversial. A recent report by the International Agency for Research on Cancer (IARC) concluded that no consistent association exists between DDT exposure and breast cancer, yet stressed that there was a lack of existing evidence to allow for the determination of the effects of early-life exposure to DDT. It has been hypothesized that exposure to DDT during critical periods of breast development may increase breast cancer risk. We hypothesized that perinatal DDT exposure would result in shortened latency of spontaneous mammary tumorigenesis and accelerated growth of mammary tumors and increase the incidence of lung metastasis. To test the effect on mammary tumor early progression and growth as well as lung metastasis, C57BL/6J female mice, pregnant as a result of mating with B6.FVB-Tg(MMTV-PyVT)634Mul/LellJ male mice, were administered DDT from gestational day 11.5 to postnatal day 5 to produce circulating levels of DDT in dams within the prenatal range associated with breast cancer in adult daughters. This perinatal DDT exposure significantly accelerated the development of palpable mammary tumors (hazard ratio = 3.7 (95% confidence interval 2.0-6.8; p&lt;0.0001). We also aimed to study possible mechanisms for DDT increasing mammary cancer risk, including alterations in puberty tempo and the presence of breast cancer risk factors associated with impaired metabolism. We found that mice exposed to DDT perinatally had increased terminal end buds in their mammary glands late in puberty (postnatal day 63, p&lt;0.05). Tumor-free mice exposed to DDT perinatally also had significantly elevated circulating glucose levels (p&lt;0.05). The risk of mammary cancer associated with perinatal DDT exposure observed in mice closely mirrors that observed in women previously. Our findings raise the possibility that perinatal DDT exposure may increase risk of breast cancer through its effects on pubertal mammary gland development and/or on glucose homeostasis. Future research to further evaluate whether these effects are mechanisms by which perinatal DDT exposure accelerates breast tumorigenesis is highly warranted.
Citation Format: Tomoko Ishikawa, Jason Tong, Alexander Borowsky, Robert Cardiff, Michele La Merrill. Perinatal DDT exposure shortens latency of mouse mammary tumorigenesis [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 A48.