bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5374: Amentoflavone induces apoptosis and promotes G1 phase cell cycle arrest through regulating p53 pathway in HT29 human colorectal cancer
Authors: Ku Hsiang-Ju , Chang Yuan , Chiang I-Tsang , Hsu Fei-Ting 
Published: June 2022

Abstract
Amentoflavone (AF) is a nature diflavonoid compound that could extract from Ginkgo biloba and Chamaecyparis obtusa. AF had been proven with many biological properties, including anti-oxidant activity, anti-inflammatory, and could also inhibit NF-κB mediating apoptosis to achieve anti-tumor effects in hepatocellular carcinoma. p53, a tumor suppressor gene that could inhibit cell division and proliferation through regulating with cell cycle and apoptosis related molecules. Patients with p53 gene mutation were often resistant to current standard treatment in clinic. Several studies also reported that the activation of p53 could induce apoptosis in colorectal cancer (CRC). Currently, there is no study determine whether AF can inhibit the growth of colorectal cancer by upregulating p53 gene expression. The aim of this study was to investigate the anticancer effect and the underlying mechanism of AF in CRC in vitro and in vivo. First, we indicated the cytotoxic effect was induced by AF in human CRC (HT29) cells. The suppression of metastasis ability including migration and invasion were found to be suppressed by AF treatment group using transwell assay. Also, in colony formation assay, AF inhibited the proliferation of CRC cells. The tumor suppressor gene p53 was upregulating with AF treatment, and the cell cycle related protein, such as CyclinD1 and CDK4 were all downregulated by AF which identified by Western blotting assay. Additionally, AF induced apoptosis in CRC cells were detected by Western blotting and flow cytometry with cleaved caspase-3, -8, -9 and Annexin V/PI assay. Moreover, Western blotting results indicated that DNA damage proteins (cleaved PARP-1 and ATM) were upregulated by AF. The nucleus translocation of caspase-dependent mitochondria initiated apoptotic protein (EndoG and AIF) were induced by AF in CRC cells. In animal experiments, the CRC tumors volume were effectively reduced in AF treatment groups as compared to non-treated control. In summary, AF mediated anti-CRC effects, such as inhibiting cell proliferation, suppressing migration/invasion ability, inducing apoptosis and triggering DNA damage is associated with the induction of p53.
Citation Format: Hsiang-Ju Ku, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu. Amentoflavone induces apoptosis and promotes G1 phase cell cycle arrest through regulating p53 pathway in HT29 human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5374.
Abstract 5407: Targeting NRF2 using specific inhibitor brusatol sensitized esophageal adenocarcinoma cells to cisplatin through inducing ferroptosis
Authors: Peng Dunfa , Hu Tianling , Chen Lei , Lu Heng , Zhu Shoumin , El-Rifai Wael 
Published: June 2022

Abstract
Background: The incidence rate of the esophageal adenocarcinoma (EAC) has increased rapidly among men during the past four decades in the USA and western countries while the 5 year survival rate is still below 20%. Traditional chemotherapy is still the main stream strategy in treatment of EAC patients. However, chemo-resistance usually develops that finally leads to failure of treatments. NFE2-related factor 2 (NRF2) is the master regulator of cellular anti-oxidant properties that maintains cell viability and cellular homeostasis. Overexpression of NRF2 in human cancers are associated with drug-resistance and poor prognosis.
Methods and Results: NRF2 protein levels are higher in several EAC cell lines, as compared to BE cell lines (CPA, BAR10T) and normal esophageal squamous cell lines, using Western blot analysis. We confirmed NRF2 overexpression in primary EAC samples, using immunohistochemistry on a tissue microarray that contained 76 EACs. Brusatol is an NRF2 specific inhibitor originated from natural plant. Administration of Brusatol in EAC cells significantly inhibited NRF2 ARE luciferase activity and reduced gene expression of NRF2 target genes such as GR, HO1, GSTM2, GPX3 and GPX4, resulting in a significant increase in cellular ROS levels, which were further increased by treatment with CDDP with subsequent increase in cancer cell death. Further investigation revealed that Brusatol significantly increased lipid peroxidation levels as detected by immunofluorescence assay and flow cytometry and resulted in significant ferroptosis, in particular in combination with CDDP treatments. We confirmed that Brusatol in combination with CDDP significantly suppressed tumor growth in a xenografting mice model.
Conclusion: Constitutive overexpression of NRF2 in EAC cells favors tumor cell survival and drug resistance. NRF2 specific inhibitor may synergize with traditional chemotherapeutic drugs by inducing lipid peroxidation and ferroptosis in EAC.
Citation Format: Dunfa Peng, Tianling Hu, Lei Chen, Heng Lu, Shoumin Zhu, Wael El-Rifai. Targeting NRF2 using specific inhibitor brusatol sensitized esophageal adenocarcinoma cells to cisplatin through inducing ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5407.
Abstract 5424: Selection of RP3D of xevinapant in combination with CRT in patients with LA SCCHN
Authors: Vugmeyster Yulia , Ravula Abhigyan , Rouits Elisabeth , Diderichsen Paul M. , Kleijn Huub J. , Goteti Kosalaram , Schroeder Andreas , Venkatakrishnan Karthik 
Published: June 2022

Abstract
Xevinapant, an antagonist of Inhibitor of Apoptosis Proteins (IAPs) showed significant improvement in locoregional control at 18 months (LRC18; primary endpoint), overall survival (OS) and progression-free survival (PFS) at an oral dose of 200 mg/day given on days 1-14 every 3 weeks in combination with CRT versus CRT with placebo in a phase II trial in patients with high-risk LA SCCHN (NCT02022098). In the dose escalation (DE) part of NCT02022098, 200 mg/day was the maximum tolerated dose and a trend of dose-response for efficacy in the 100-300 mg/day dose range was observed. The phase III TrilynX study of xevinapant plus CRT in patients with LA SCCHN is currently enrolling (NCT04459715). Here we present the integrated rationale for the recommended phase III dose (RP3D) of xevinapant 200 mg/day based on all available clinical and preclinical data and modeling and simulation (M&S).
At the RP3D, ~95% of the patients are projected to have free trough concentrations above in vitro IC50 for cIAP1 degradation (a pharmacodynamic [PD] marker), based on a population (pop) PK M&S. In patients, average free concentration over the dosing interval at RP3D is similar to that associated with maximal efficacy in preclinical SCCHN models. Pop PK/PD M&S
suggests that maximal cIAP1 degradation is maintained in PBMCs with 100-200 mg/day doses during the 14-day dosing period, with a trend of dose-response for the partial cIAP1 degradation at the end of the 3-week cycle.
Exposure response (E-R) analyses were conducted based on the pooled datasets of DE and randomized parts of study NCT02022098 (n=62 treated with xevinapant). Logistic regressions showed that probabilities of LRC18, overall response, complete response, and the composite safety endpoint of “mucositis and/or dysphagia” increase with increasing exposure (p&lt;0.05). Statistically significant E-R relationships were not discernible for any other evaluated safety endpoints or for PFS, OS, or duration of LRC. However, patients in higher exposure subgroups showed a longer duration of LRC.
In summary, integration of preclinical pharmacology, clinical efficacy and safety profiles, clinical PK/PD, popPK, and E-R analyses support the RP3D selection of xevinapant at 200 mg/day administered on days 1-14 every 3 weeks with concomitant CRT, allowing for successive dose reductions to 150 mg and 100 mg for management of toxicities.
Citation Format: Yulia Vugmeyster, Abhigyan Ravula, Elisabeth Rouits, Paul M. Diderichsen, Huub J. Kleijn, Kosalaram Goteti, Andreas Schroeder, Karthik Venkatakrishnan. Selection of RP3D of xevinapant in combination with CRT in patients with LA SCCHN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5424.
Abstract 5447: Enhanced antitumoral effect of the glycosylated 4-methylumbelliferone in hepatocellular carcinoma
Authors: Weiz Gisela , Gonzalez Alina L. , Piccioni Flavia , Fusco Mariel , Gutiérrez Marco Diaz , Mazzolini Guillermo , Breccia Javier D. , Malvicini Mariana , Molejon Maria I. 
Published: June 2022

Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, and is particularly refractory to the available therapeutic drugs. Unfortunately, curative treatments such as surgery, liver transplantation, or ablation are reserved for early stages and can only be applied in less than 30% of the patients with HCC. Glycosylation can be a potent and interesting strategy for drug delivery to a specific target. We enzymatically synthesized a glycosylated derivative of the coumarin 4-methylumbelliferone (4MU), namely 4MUR.The antitumoral effect of 4MUR in comparison with the aglycone 4MU was evaluated onto liver cancer cells. Cellular toxicity was determined on murine liver tumor cell lines as well as non-hepatic tumoral cells. Tumor cell lines were significantly more sensitive than non-tumoral cells to the glycosylated molecule in a dose-dependent manner (p&lt;0.05). 4MUR was incorporated mostly into tumoral cells by the interaction with the asialoglycoprotein receptor (ASGPR), which is overexpressed in liver tumor cells. Hyaluronic acid (HA) is the major component of the extracellular matrix (ECM). It is produced at the plasma membrane by three hyaluronan synthases (HAS1, 2 and 3), which couple glucuronic acid and N-acetylglucosamine into a linear polymer using the corresponding UDP-sugars (UDP-GlcUA and UDP-GlcNAc) as substrates. Unlike 4MUR, the glucuronidation of 4MU competitively inhibits chain elongation of HA. Furthermore, 4MUR treatment regulates the levels of HAS2 and HAS3 expression in the tumoral cell line. Finally, 4MUR treatment induced apoptosis cell death in tumoral cells. Our results suggest that the 4MUR is safe and effective against liver tumor cells via a specific targeting to ASGPR receptor and decreasing HA synthesis.
Citation Format: Gisela Weiz, Alina L. Gonzalez, Flavia Piccioni, Mariel Fusco, Marco Diaz Gutiérrez, Guillermo Mazzolini, Javier D. Breccia, Mariana Malvicini, Maria I. Molejon. Enhanced antitumoral effect of the glycosylated 4-methylumbelliferone in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5447.
Abstract 5448: Synergistic antitumor effect of ONC201, radiotherapy and temozolomide in glioblastoma mouse orthotopic models
Authors: Zhou Lanlan , Wu Jinxuan Laura , Safran Howard P. , El-Deiry Wafik S. 
Published: June 2022

Abstract
Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults with a median survival of just over a year and a two-year survival of about 30%. Only 10% of people survive five years of this grade IV cancer. Standard of care therapy comprises maximal safe surgical resection followed by adjuvant alkylating agent temozolomide (TMZ) and radiotherapy conferring a median survival time of 14.6 months compared with 12.1 months for GBM patients treated with radiotherapy alone. First-in-class small-molecule imipridone ONC201 has shown efficacy in glioblastoma models in vitro, in vivo, and ex vivo. It is also orally active and is administered once every week, a favorable dosing schedule for patients. We hypothesized that ONC201 may synergize with radiotherapy and Temozolomide in GBM in vitro and in vivo. We previously reported that ONC201 synergizes with radiotherapy and/or TMZ to inhibit cell viability and colony formation and induce ER stress and apoptosis in GBM cells. To pursue this promising combinational therapy in vivo, we established GBM mouse orthotopic models through intracranial injection of luciferase expressing GBM cells U-251-LUC with a KOPF model 940 small animal stereotaxic frame and a Stoelting Quintessential Stereotaxic Injector. Tumor formation was confirmed with bioluminescence imaging. Randomized treatment group mice have received weekly treatment of ONC201 (100 mg/kg p.o.) and/or radiotherapy (2 Gy local irradiation) and/or TMZ (20 mg/kg i.p.) for four weeks. We observed the triple combination of ONC201 and radiotherapy and TMZ significantly reduced tumor burden and prolonged survival compared to dual combinations in GBM mouse orthotopic model U-251-LUC. We are currently exploring the synergistic mechanisms of triple combination including TRAIL signaling pathway, ISR, dopamine receptors and mitochondrial ClpXP, and potential pharmacodynamic biomarkers from in vivo samples. Our study suggests that the investigational triple combination therapy of ONC201 and radiotherapy and TMZ is going to be an important option for patients with GBM.
Citation Format: Lanlan Zhou, Jinxuan Laura Wu, Howard P. Safran, Wafik S. El-Deiry. Synergistic antitumor effect of ONC201, radiotherapy and temozolomide in glioblastoma mouse orthotopic models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5448.
Abstract 5451: New organoselenium compounds with cytotoxic activity in vitro and in vivo towards colon cancer
Authors: Ramos-Inza Sandra , Aliaga Cesar , Raza Asif , Encío Ignacio , Sharma Arun , Sanmartín Carmen , Plano Daniel 
Published: June 2022

Abstract
Colon cancer is currently the third most common diagnosed cancer and the second leading cause of cancer death worldwide. The inclusion of a selenium atom (Se) in organic molecules has been shown to be a valid approximation in the design of novel chemotherapeutic agents with antitumoral activity. On the other hand, non-steroidal anti-inflammatory drugs (NSAIDs) have gained interest in recent years in terms of their chemopreventive and chemotherapeutic use for cancer treatment whether they are evaluated alone, as a combination therapy, or in the form of structurally modified analogs. Considering these findings, we have designed five novel NSAID derivatives containing Se in their structure. The cytotoxicity and selectivity of the new compounds were evaluated in a panel of 10 cancer cell lines including breast, prostate, lung, and colon cancer, and in two non-malignant cell lines. Compound 5 was the most cytotoxic derivative with IC50 values below 10 µM in all the cancer cell lines tested, and it was also the most selectively toxic towards cancer cells while sparing the non-malignant cell lines. The efficacy of compound 5 in vivo was assessed in a subcutaneous colon cancer xenograft mouse model and it showed a significant inhibition of the tumor growth. Taken together, this work supports that the novel Se-NSAID combination provides a feasible frame to develop new agents with potent antitumoral properties
Citation Format: Sandra Ramos-Inza, Cesar Aliaga, Asif Raza, Ignacio Encío, Arun Sharma, Carmen Sanmartín, Daniel Plano. New organoselenium compounds with cytotoxic activity in vitro and in vivo towards colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5451.
Abstract 5465: Discovery of LXRβ selective agonists promote immune cell activation and induce tumor growth inhibition in syngeneic tumor model
Authors: Pujala Brahmam , Sathe Balaji Dashrath , Gupta Ashu , Danodia Abhinandan , Soni Sanjeev , Kumar Vivek , Saeed Uzma , Chakravarty Sarvajit 
Published: June 2022

Abstract
Nuclear receptors, liver X receptor-α (LXRα) and liver X receptor-β (LXRβ), are considered master regulators of lipid homeostasis and play pivotal roles in several physiological and pathological processes ranging from energy supply, cardiovascular, immunity, neurodegenerative disorders and cancer. Therapeutic agonism of the LXR/ApoE axis has proven to promote anti-tumor immunity by targeting immunosuppressive innate immune cells.1 LXR-ApoE pathway regulate the innate immune system in cancer, via modulation of the activity and abundance of myeloid derived suppressor cells (MDSC) and DCs. ApoE binds to Lipoprotein receptor-related protein (LRP) on MDSC induces apoptosis, thus resulting in immune-mediated anti-tumor activity of LXR agonists. Development of LXR agonists as therapeutics has proven quite challenging due to their precipitation of hepatic steatosis and hypertriglyceridemia. Most of the lipogenic effects of LXR agonists are mediated through LXRα.2 LXR subtype-specific agonists (LXRβ specific), may overcome hepatic triglyceride accumulation and (transient) hypertriglyceridemia. Here we report the discovery of IBS624 which is the most selective LXR agonist till date, &gt;185X selective for LXRβ over LXRα. IBS-624 has reasonable exposure in mouse with 40% oral bioavailability. IBS-624 was well tolerated at 100mg/kg, BID for 14 days with no increase in triglycerides and neutropenia. IBS-624 has shown efficacy in MC38 colon cancer model as single agent as well as in combination with Checkpoint inhibitor. 1. Cell. 2018, 172(4): 825-840. 2. Biochemical pharmacology 2006, 71, 453-463
Citation Format: Brahmam Pujala, Balaji Dashrath Sathe, Ashu Gupta, Abhinandan Danodia, Sanjeev Soni, Vivek Kumar, Uzma Saeed, Sarvajit Chakravarty. Discovery of LXRβ selective agonists promote immune cell activation and induce tumor growth inhibition in syngeneic tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5465.
Abstract 5480: Aristolochic acid as a scaffold for antitumor drug development
Authors: Hashimoto Keiji , Chennamshetti Rajesh , Bonala Radha , Johnson Francis , Grollman Arthur P. , Sidorenko Viktoriya S. 
Published: June 2022

Abstract
We have synthesized an analog of aristolochic acid (AA) with potent growth inhibitory activity in various human cancer cell lines and report here on mechanistic studies of this potential therapeutic. AA is a natural product and the main active principle of Aristolochia plants, a known source of antitumor agents. In 1964 due to nephrotoxicity, drug development efforts with AA were terminated following Phase I clinical trial in patients with terminal cancer of different origin. Structure activity studies of AA species allowed us to select a structural analog of AA (RJ-34) that lacks the determinants responsible for the renal toxicity and carcinogenicity of the parent compound. Building further on our experience with AA molecules, we developed a synthetic approach that affords efficient high-yield synthesis of RJ-34. Its structure and purity has been confirmed by high-performance liquid chromatography, liquid chromatography coupled with two-stage mass spectrometry and high resolution nucleic magnetic resonance. Sulforhodamine B assay revealed that RJ-34 has growth inhibitory activity in A549 and HCT-15 human cancer cell lines comparable to or stronger than that of paclitaxel or topotecan. At five nanomolar, RJ-34 inhibited DNA synthesis and cut the growth of A549 cells by 50%, leading to cell cycle arrest in G1/M and G2/S, with apparent apoptosis at concentrations greater than 200 nanomolar. Notably, protein synthesis in cultured cells, as evaluated by puromycin labelling, remained unaffected. RJ-34 was screened against the NCI-60 cell line panel - encompassing sixty human cancer cell lines from various tissues - providing clues to its mechanisms of action; namely, that RJ-34 acts through inhibition of DNA topoisomerases I and II and/or DNA intercalation. Follow-up studies using purified calf Topo I and human Topo II alpha and various plasmid substrates confirmed the role of RJ-34 as a DNA intercalator and human Topoisomerase II alpha poison. The pattern of activity of RJ-34 in the NCI-60 panel was distinct from that of AA and aristolactam - another related compound - suggesting that RJ-34 acts by mechanisms distinct from AA. In summary, RJ-34— a non-nephrotoxic analog of aristolochic acid— has a potent growth inhibitory activity in various human cancer cell lines with a mechanism of action different from the parent AA. Moving forward, pre-clinical pharmacokinetics, safety and efficacy studies are necessary to establish the potential of RJ-34 for development as an anticancer therapeutic.
Citation Format: Keiji Hashimoto, Rajesh Chennamshetti, Radha Bonala, Francis Johnson, Arthur P. Grollman, Viktoriya S. Sidorenko. Aristolochic acid as a scaffold for antitumor drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5480.
Abstract 5482: Natural product inhibitor of Stat3, G6PD, and TrxR1 functions induces an early oxidative stress and pyroptosis, and a late-stage DNA damage and cell cycle arrest to block tumor growth in human breast cancer models
Authors: Zhu Yinsong , Dickinson Cody F. , Yang Justin , Datanagan Kyrstin , Zhai Ning , Yue Peibin , Lopez-Tapia Francisco , Tius Marcus A. , Turkson James 
Published: June 2022

Abstract
Bioactive natural products have led to new drugs or been the inspiration for developing new treatments. Signal transducer and activator of transcription (STAT)3 is a an oncogene that has been implicated in many human cancers. We report that the hirsutinolide natural product, R001, blocks STAT3 DNA-binding activty in vitro. Treatment with R001 of the human triple-negative breast cancer (TNBC) cells, MDA-MB-231 and MDA-MB-468 led to the concurrent inhibition of constitutively-active STAT3 and the expression and activities of glucose-6-phosphate 1-dehydrogenase (G6PD) and thioredoxin reductase (TrxR)1, early suppression of glutathione (GSH), and the induction of reactive oxygen species (ROS), which peaked at 6-24 h post R001-treatment. In the short term, R001-treated TNBC cells showed evidence of pyroptotic cell death. Prolonged treatment of TNBC cells with R001 led to DNA damage and G2/M-phase cell cycle arrest, which are late-stage responses that were preceded by the suppression of ATM-Chk2-Cdc25c pathway, and the induction of p21 and γH2AX phosphorylation by the natural product. Accordingly, R001 suppressed the viable cell numbers, colony formation, growth in 3D-matrigel, and the migration of MDA-MB-231 and MDA-MB-468 cells in vitro. The oral administration of R001 at 5 mg/kg signficantly inhibited growth of human MDA-MB-468 xenografts in mice. Results together show that R001 inhibits STAT3, G6PD and TrxR1 functions that lead to early oxidative stress and pyroptosis and late-stage DNA damage and cell cycle arrest, which collectively cause tumor cell death and tumor growth inhibition in human TNBC models.
Citation Format: Yinsong Zhu, Cody F. Dickinson, Justin Yang, Kyrstin Datanagan, Ning Zhai, Peibin Yue, Francisco Lopez-Tapia, Marcus A. Tius, James Turkson. Natural product inhibitor of Stat3, G6PD, and TrxR1 functions induces an early oxidative stress and pyroptosis, and a late-stage DNA damage and cell cycle arrest to block tumor growth in human breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5482.