Anticancer Drug Treatment Research Articles

Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo

Knockdown of GH receptor (GHR) in melanoma cells in vitro downregulates ATP-binding cassette-containing (ABC) transporters and sensitizes them to anti-cancer drug treatments. Here we aimed to determine whether a GHR antagonist (GHRA) could control cancer growth by sensitizing tumors to therapy through downregulation of ABC transporters in vivo. We intradermally inoculated Fluc-B16-F10 mouse melanoma cells into GHA mice, transgenic for a GHR antagonist (GHRA), and observed a marked reduction in tumor size, mass and tumoral GH signaling. Moreover, constitutive GHRA production in the transgenic mice significantly improved the response to cisplatin treatment by suppressing expression of multiple ABC transporters and sensitizing the tumors to the drug. We confirmed that presence of a GHRA and not a mere absence of GH is essential for this chemo-sensitizing effect using Fluc-B16-F10 allografts in GH knockout (GHKO) mice, where tumor growth was reduced relative to that in GH-sufficient controls but did not sensitize the tumor to cisplatin. We extended our investigation to hepatocellular carcinoma (HCC) using human HCC cells in vitro and a syngeneic mouse model of HCC with Hepa1-6 allografts in GHA mice. Gene expression analyses and drug-efflux assays confirm that blocking GH significantly suppresses the levels of ABC transporters and improves the efficacy of sorafenib towards almost complete tumor clearance. Human patient data for melanoma and HCC show that GHR RNA levels correlate with ABC transporter expression. Collectively, our results validate in vivo that combination of a GHRA with currently available anti-cancer therapies can be effective in attacking cancer drug resistance.

Abstract 892: Single-cell RNA sequencing of patient-derived organoid reveals treatment-induced tumor resistance through cancer stem cells

Abstract It is thought that a few treatment-resistant cells form heterogenous recurrences and metastases, but what cells make complex tumor lineage is unexplored in colorectal cancer (CRC). To elucidate the cells that escape from treatment and form recurrences and metastases, the gene expression landscape, and drug susceptibility were explored using patient-derived organoids (PDOs). Drug sensitivities of 16 PDOs including eight PDOs derived from patients with distant metastases were evaluated. t-SNE analysis clearly showed four clusters, including two clusters based on response to therapy (good and poor). RNA sequence analysis showed that poor-response PDOs were enriched in gene sets related to distant metastasis, recurrence, and treatment resistance compared with good-response PDOs. Expression of nine genes (CBS, E2F8, GCNT1, NETO2, PLPP5, POU5F1, XRCC2, RECQL4, and ZNF681) were characteristic in the poor-response PDOs. Among them, we focused on POU5F1 gene that characterized liver metastasis in CRC from our previous report. Further analysis revealed that POU5F1-positive cells survive after anticancer drug treatment, and they were produced from POU5F1-expressing cells, not POU5F1-negative cells. Notably, isolated single POU5F1-expressing cell produced a heterogeneous population of cells expressing various differentiation markers both in vitro and in vivo. Single POU5F1-expressing cell also reconstructed ductal structure with mucus-producing ability. Cells produced from POU5F1-expressing cells were thought to construct tumor diversity remaining various differentiation stage. Single-cell RNA sequencing was performed to reveal the heterogeneous population with treatment resistance. The seven characteristic clusters were identified and the number of cells in clusters 2, 4, and 6 increased at the time of tumor re-growth after anticancer drug treatment. Cluster 2 was characterized by cell-cycle score. When cluster 4 was set as the root of the proliferative trajectory, the trajectory of cluster 4→3→6 emerged with characteristic gene expression profiles. The Wnt signaling pathway was enriched in cluster 4, suggesting stem cell characteristics. Moreover, Glycolysis, HIF-1 signaling, and ferroptosis pathways, which are also reported as properties of persister cells were enriched in cluster 6. Herein, we report the features derived from single-cell RNA seq analysis and further examinations in vitro, in vivo, and in clinical specimens. Citation Format: Shiki Fujino, Aya Ito, Masayoshi Yasui, Chu Matsuda, Masayuki Ohue, Masafumi Horie, Shinichi Yachida, Yuichiro Doki, Hidetoshi Eguchi, Norikatsu Miyoshi. Single-cell RNA sequencing of patient-derived organoid reveals treatment-induced tumor resistance through cancer stem cells [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 892.

Abstract 3709: Synergistic activity of ABT-263 and ONC201 against solid tumor cell lines is associated with suppression of BAG3, Mcl-1, pAkt, and upregulation of Noxa along with Bax cleavage during apoptosis

Abstract There is an urgent need for the development of novel therapeutic approaches that can address the complex nature of cancer, including resistance to therapy. A major underlying cause of the resistance is the evasion of cell death following anti-cancer drug treatment. A great deal of progress has been made in the discovery and early development of cancer therapeutics that target cell death via the intrinsic or extrinsic cell death pathways. Two such drugs are ABT-263 and ONC201. ABT-263 is a small molecule that targets the pro-apoptotic cell death of tumor cells by blocking the anti-apoptotic function of BCL-XL and BCL-2; ONC201/TIC10 is a first-in-class small molecule originally discovered as a TRAIL-inducing compound. Previous studies have found that a mechanism of resistance to ABT-263 involves upregulation of anti-apoptotic Mcl-1 in ABT-263-treated tumors, while the efficacy of ONC201 is limited by BCL-2 overexpression. Given that ONC201 is known to downregulate Mcl-1 expression and that BCL-2 is a target of ABT-263, the combination of the two drugs has great synergistic potential. ONC201 and ABT-263 been tested in glioblastoma; however, ABT-263 is not able to cross the blood-brain barrier, and the combination of ONC201 and ABT-263 has not been tested in other solid tumors. It remains a gap in the field to test this combination therapy in tissues to which ONC201 and ABT-263 are bioavailable. We explored the combination of TRAIL-inducing compound ONC201/TIC10 and BCL-xl/BCL-2 inhibitor ABT-263 to target the extrinsic and intrinsic apoptotic pathways, respectively, in solid tumor cell lines (N=13) derived from different tissues (colon, prostate, lung, breast, ovary, bladder). We found an IC50 range of 0.83-20.10 μM for ONC201 and 0.06-14.75 μM for ABT-263 among the 13 cell lines. We show that combination of ONC201 and ABT-263 produces a strong synergistic effect leading to tumor cell death across the 1cell line panel, with maximum synergy scores ranging from 13.56-52.23 (scores were calculated using SynergyFinder; scores 0-10 indicate additive effects, while scores >10 indicate synergism), and that the combination is not toxic to human fibroblast cells. We also found that the combination of these two agents resulted in caspase activation and PARP cleavage consistent with induction of apoptosis, and that these effects where over and above individual drug effects. Combination therapy-induced cell death correlated with decreased levels of Mcl-1, BAG3, pAkt, and upregulation of Noxa along with Bax cleavage during apoptosis. Our data provide evidence for synergy from the combination of ONC201 and ABT-263 against human solid tumor cell lines associated with alterations in cell death and pro-survival mediators. The combination of ONC201 and ABT-263 merits further exploration in vivo in a variety of solid malignancies. Citation Format: Francesca R. Di Cristofano, Mara Fong, Lanlan Zhou, Wafik S. El-Deiry. Synergistic activity of ABT-263 and ONC201 against solid tumor cell lines is associated with suppression of BAG3, Mcl-1, pAkt, and upregulation of Noxa along with Bax cleavage during apoptosis [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 3709.

Healthcare resource utilization and medical costs in patients with terminal cancer during best supportive care.

Patients with terminal cancer have different physical symptoms, prognoses, emotional distress, and end-of-life care plans from those receiving aggressive chemotherapy; few studies have assessed healthcare resource use in these patients. Therefore, this study aimed to assess healthcare resource utilization and medical costs incurred during best supportive care after the last anticancer drug treatment in patients with terminal cancer. This retrospective observational study was conducted using national sample cohort data from the National Health Insurance Service in South Korea. Only patients with cancer who were treated with the last anticancer drugs from January 1, 2006, to June 30, 2015, were included in the study. The period of best supportive care was defined as the time from the date of use of the last anticancer drug to death. Healthcare resource utilization and medical costs were estimated during the best supportive care. A generalized linear model with a log-link function and gamma distribution was used to evaluate the impact of demographic and healthcare utilization factors on total medical costs. Among the 2,480 patients in the study, 93.9% were hospitalized, and hospitalization days (30.8 days) accounted for 39.7% of the surviving period (77.5 days). The proportions of intensive care unit admissions and emergency department visits were 15.8% and 18.9%, respectively. The average total medical cost per patient was $6,310, with the inpatient cost ($5,705) being approximately 9.4 times higher than the outpatient cost ($605). The length of hospitalization had the greatest impact on the total medical costs. Pancreatic cancer had the highest proportion of patients who were hospitalized (97.4%) and the highest medical cost ($7,702). Hospital-based resources were utilized by most patients with terminal cancer, and hospitalization was a major driver of the total medical cost. An alternative system for hospitalization should be developed to support patients with terminal cancer, both clinically and financially.

Glutathione Peroxidase 4 as a Therapeutic Target for Anti-Colorectal Cancer Drug-Tolerant Persister Cells.

BackgroundDespite the effectiveness of chemotherapy and targeted therapy for colorectal cancer, drug resistance drives therapy failure and tumor relapse. Increasing evidence has suggested that cancer cells can enter a reversible drug-tolerant persister state to survive chemotherapy or targeted agents. However, the traits and treatable vulnerabilities of anti-colorectal cancer drug-tolerant persister cells is not yet known.MethodsIn this study, we established 5-fluorouracil and AZ628-tolerant persister cell models in two colorectal cancer cell lines, namely HCT116 and SW620, and revealed the characteristics of colorectal cancer persister cells by cell viability assay and flow cytometry. We investigated the efficacy and mechanism of ferroptosis inducers RSL3 and FIN56 on persister cells, which are glutathione peroxidase 4 inhibitors. In the xenograft mouse model, we further evaluated the inhibitory effect of RSL3 on tumor regrowth.ResultsColorectal cancer persister cells, which were enriched in the residual cancer cell population, exhibited reduced drug sensitivity, were largely quiescent and expressed high levels of stem cell-related genes and mesenchymal markers but not epithelial markers. The persister cells were more sensitive and underwent ferroptosis induced by glutathione peroxidase 4 inhibitors. Mechanistically, glutathione peroxidase 4 and ferrous iron, which are pivotal ferroptosis regulators, were upregulated in residual cells or tumors, and were hence potential therapeutic targets of persister cells. In the xenograft model, we confirmed that inhibition of glutathione peroxidase 4 restrained tumor regrowth after discontinuation of anti-cancer drug treatment. Moreover, biopsies obtained from patients with colorectal cancer undergoing neoadjuvant chemoradiotherapy revealed upregulated glutathione peroxidase 4 and ferritin heavy chain 1. High glutathione peroxidase 4 expression correlates with a worse prognosis in colorectal cancer patients.ConclusionsOur work reveals that the upregulated glutathione peroxidase 4 and ferrous iron in anti-colorectal cancer drug-tolerant persister cells were potential therapeutic targets. Glutathione peroxidase 4 inhibition combined with chemotherapy or targeted therapy may be a promising therapy for colorectal cancer.

A novel drug combination strategy that redesigns the pharmacological management of oral cancer.

e18053 Background: Biofilm formation is a continuous process in oral cancer patients, despite proper extirpation/elimination of a bacterial plaque via a surgical procedure or antibiotic treatment. Also, elimination of a bacterial plaque does not necessarily remove extant bacterial antigen-stimulated oral cancer cells. Therefore, combination drug treatment may be an appropriate approach to elucidate the confounding effects of bacterial antigens on anti-cancer drugs. Methods: Our drug combination strategy addressed both Gram-positive (Lipoteichoic acid [LTA]) and Gram-negative (Lipopolysaccharide [LPS]) bacterial antigens, to determine the effect of anti-cancer drugs on LPS/LTA/LPS+LTA-stimulated preclinical oral cancer models (SCC4, SCC9, SCC25, and Cal 27). The drug combination strategy was designed in six phases of treatment. In phase 1, plated cells were treated with different combinations of bacterial antigens in combination with anti-cancer drugs. In the phases 2 and 3, inhibitory drugs were introduced in the presence of bacterial antigens after 24 hours and 72 hours of bacterial antigen stimulation. In phases 4 and 5, inhibitory drugs were added after 24 hours and 72 hours of bacterial antigen stimulation. In phase 6, inhibitory drugs were applied in the absence of, and without stimulation with, bacterial antigens. Metabolic assays, reverse transcription quantitative PCR, Western blot, Proteome Profiler, apoptotic and ELISA assays were performed to validate the novel drug combination strategy. Results: Anti-cancer drug treatment on preclinical oral cancer models resulted in 43.6% ± 3.3% of precancerous models being apoptotic. To mimic pre-existing unhygenic conditions in oral cancer patients, prior stimulation of preclinical model with LPS+LTA 72 hours before drug treatment, reduced apoptosis to 32.2% ± 1.1% of cells. Apoptosis was almost annulled (2.98% ± 0.3%; p < 0.01) when drug treatment was carried out along with bacterial antigens. Treatment with drugs in the absence of bacterial antigens resulted in significantly more apoptotic cells than in presence of bacterial antigens (p < 0.0001). Metabolic and viability assay showed similar results like apoptotic assay. Conclusions: Bacterial antigens mimic the presence of Gram-negative and Gram-positive bacteria and thus severely affect the efficacy of anti-cancer drugs. The novel drug combination strategy redesigns the pharmacological management of oral squamous cell carcinoma.

Effect of DPP-4 inhibitors on erectile dysfunction caused by vincristine in rats

ABSTRACT Introduction Various chemotherapeutic agents are administered to cancer patients worldwide. Previously, an analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database showed that vincristine (VCR) increased the risk of erectile dysfunction (ED), as reported in the world meeting on Sexual Medicine 2018. As such, countermeasures for late complications after anticancer drug treatment are required. Neuropathy is a well-known side effect of VCR; however, in recent years, it has been reported that DPP-4 inhibitors improve neuropathy. Objective To investigate the effect of DPP-4 inhibitors to ED caused by VCR in rats. Methods Twelve-week-old male Wistar ST rats were separated into Control, VCR, and VCR+DPP-4i groups. VCR (0.1 mg/kg) was intravenously administered on days 1, 8, 15, and 22 in the VCR and VCR+DPP-4i groups. Two types of long-term preparations, toleragliptin (TGP; 3 mg/kg/week, po.) and omaligliptin (OGP; 3 mg/kg/week, po.), were examined for DPP-4i. Erectile function was tested using intracavernous pharmacotherapy (ICP) measurements, and endothelial function was tested through an isometric tension study. Additionally, mRNA expressions were tested using real-time PCR. Results After the 4-week observation period, the ICP/mean arterial pressure (MAP) ratio in the VCR group (0.42 ± 0.04) was significantly decreased compared to the Control group (0.72 ± 0.05) (P <0.01). The ICP/MAP ratio in the VCR+TGP group (0.64 ± 0.02) increased significantly compared to the VCR group (P <0.05), however the ICP/MAP ratio in the VCR+OGP (0.50 ± 0.08) did not increase significantly compared to the VCR group (P > 0.05). Real-time PCR analysis showed that the catalase, VEGF, MCP-1, and PAI-1 mRNA expressions were increased, while the IL-6 mRNA expression decreased significantly in the VCR+TGP and VCR+OGP groups. In contrast, the nNOS mRNA expression level was higher in the VCR+TGP group than in the VCR+OGP group. Conclusions In this study, we determined that DPP-4 inhibitors may improve ED by VCR administration. For ED associated with VCR administration, long-term DPP-4 inhibitor TGP administration suggested a significant improvement in erectile function, but OGP did not show a significant improvement effect. An increase in antioxidant activity and a decrease in inflammatory cytokines were observed for both drugs, including a surge in vascular increase factors. In contrast, the nNOS expression level was higher in TGP, suggesting that there may be a difference in the amount of NO production via nerves. Therefore, TGP may be useful for male sexual dysfunction associated with vincristine administration. Disclosure Work supported by industry: no.

Testosterone improved the erectile dysfunction induced by anti-cancer agent doxolubicine in rats

ABSTRACT Introduction Many chemotherapeutic agents are administered to cancer patients worldwide. We previously reported at the world meeting on Sexual Medicine 2018 that doxorubicin (DOX) increased the risk of erectile dysfunction (ED) according to our analyses of the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database. We also reported that DOX decreased erectile function in a study using rats. DOX also decreased rat testosterone levels. These studies suggest a need for a new treatment method for ED associated with anticancer drug treatment. Objective To investigate the effect of testosterone administration on DOX-induced ED in rats. Methods Twelve-week-old male Wistar ST rats were separated into Control, DOX, and DOX+T groups. DOX (3 mg/kg) was intravenously administered on days 1, 8, 15, and 22 in the DOX and DOX+T groups. Testosterone undecanoate (25 mg/kg) was administered to DOX+T rats on day 1. Erectile function was tested using ICP measurements, and endothelial function was tested by assessing isometric tension. Oxidative stress (NADPH oxidase), inflammation (IL-6), and smooth muscle factor (α-SMA, Cavin-1, and Cavin-2) mRNA expression levels were tested using real-time PCR. Results After the 4-week observation period, the ICP/MAP ratio in the DOX group (0.32 ± 0.03) was significantly decreased compared to the Control group (0.72 ± 0.05) (P <0.01). The ICP/MAP ratio in the DOX + T group (0.61 ± 0.07) was increased significantly compared to the DOX group (P <0.01). According to isometric tension measurements, reactivity to acetylcholine was significantly lower in the DOX group (35.0 ± 5.1%) than in the control group (77.6 ± 7.9%), whereas reactivity in the DOX + T group (69.8 ± 8.5%) was significantly improved (P <0.05). NADPH oxidase-1 and IL-6 mRNA levels were increased in the DOX group compared to the Control group (P <0.01), and levels were decreased relative to the DOX group in the DOX+T group. α-SMA, Cavin-1, and Cavin-2 mRNA levels were decreased in the DOX group compered to the Control group. These levels were improved in the DOX+T group. Conclusions We have demonstrated in rats that androgen replacement therapy may mitigate ED induced by DOX administration. We hypothesize that administration of testosterone improves smooth muscle function and vascular endothelial cell function by suppressing oxidative stress and inflammatory response in the corpus cavernosum, and maintaining normal levels of caveolin-related factors. When androgen deficiency symptoms are observed due to administration of anticancer drugs such as DOX, androgen replacement therapy is expected to be one viable treatment option. Our study sheds light on possible treatment strategies for improving quality of life for cancer survivors. Disclosure Work supported by industry: no.

Regulation of Hippo signaling by metabolic pathways in cancer.

Hippo signaling is known to maintain balance between cell proliferation and apoptosis via tight regulation of factors, such as metabolic cues, cell-cell contact, and mechanical cues. Cells directly recognize glucose, lipids, and other metabolic cues and integrate multiple signaling pathways, including Hippo signaling, to adjust their proliferation and apoptosis depending on nutrient conditions. Therefore, the dysregulation of the Hippo signaling pathway can promote tumor initiation and progression. Alteration in metabolic cues is considered a major factor affecting the risk of cancer formation and progression. It has recently been shown that the dysregulation of the Hippo signaling pathway, through diverse routes activated by metabolic cues, can lead to cancer with a poor prognosis. In addition, unique crosstalk between metabolic pathways and Hippo signaling pathways can inhibit the effect of anticancer drugs and promote drug resistance. In this review, we describe an integrated perspective of the relationship between the Hippo signaling pathway and metabolic signals in the context of cancer. We also characterize the mechanisms involved in changes in metabolism that are linked to the Hippo signaling pathway in the cancer microenvironment and propose several novel targets for anticancer drug treatment.

DualGCN: a dual graph convolutional network model to predict cancer drug response

BackgroundDrug resistance is a critical obstacle in cancer therapy. Discovering cancer drug response is important to improve anti-cancer drug treatment and guide anti-cancer drug design. Abundant genomic and drug response resources of cancer cell lines provide unprecedented opportunities for such study. However, cancer cell lines cannot fully reflect heterogeneous tumor microenvironments. Transferring knowledge studied from in vitro cell lines to single-cell and clinical data will be a promising direction to better understand drug resistance. Most current studies include single nucleotide variants (SNV) as features and focus on improving predictive ability of cancer drug response on cell lines. However, obtaining accurate SNVs from clinical tumor samples and single-cell data is not reliable. This makes it difficult to generalize such SNV-based models to clinical tumor data or single-cell level studies in the future.ResultsWe present a new method, DualGCN, a unified Dual Graph Convolutional Network model to predict cancer drug response. DualGCN encodes both chemical structures of drugs and omics data of biological samples using graph convolutional networks. Then the two embeddings are fed into a multilayer perceptron to predict drug response. DualGCN incorporates prior knowledge on cancer-related genes and protein–protein interactions, and outperforms most state-of-the-art methods while avoiding using large-scale SNV data.ConclusionsThe proposed method outperforms most state-of-the-art methods in predicting cancer drug response without the use of large-scale SNV data. These favorable results indicate its potential to be extended to clinical and single-cell tumor samples and advancements in precision medicine.

Chemotherapeutic Risk lncRNA-PVT1 SNP Sensitizes Metastatic Colorectal Cancer to FOLFOX Regimen.

Recent studies have identified that long noncoding RNA (lncRNA) might affect the responses to anticancer drug treatment, including colorectal cancer (CRC). However, the association between single-nucleotide polymorphisms (SNPs) in PVT1 and the chemotherapy response in metastatic colorectal cancer has yet to be clarified. In this study, the PVT1 rs2278176 CT/TT genotypes were found to be associated with an increased overall survival (OS) and progression-free survival (PFS) compared with the CC genotype. Furthermore, patients harboring the rs2278176 CT/TT genotypes had a greater chance of achieving clinical benefit from 5-Fluorouracil/leucovorin combined with oxaliplatin (FOLFOX). In vivo nude mice experiments demonstrated that the CRISPR/Cas9 mediated rs2278176 C to T mutation significantly inhibited the tumorigenesis of colorectal cancer cells treated with 5-Fu, but not control DMSO treated cells. Furthermore, the apoptotic rate was significantly enhanced by treatment with 5-Fu in the CRC cells carrying with the CT/TT genotypes. Functional studies demonstrated that the PVT1 rs2278176 C to T mutation altered the binding site for hsa-miR-297, and that hsa-miR-297 downregulated Glutathione S-Transferase Alpha 2(GSTA2), a member of phase II detoxification enzyme, in an Argonaute 2(Ago2)-dependent manner. Moreover, GSTA2 levels were downregulated in the cancer tissues of patients carrying rs2278176 CT/TT genotypes. High GSTA2 expression predicted poor clinical outcome in metastatic colorectal cancer treated with FOLFOX. In conclusion, this study provided that PVT1 with rs2278176 T allele altered the binding affinity with hsa-miR-297, leading to decreased GSTA2 expression and sensitized CRC cells to FOLFOX chemotherapy, suggesting rs2278176 CT/TT genotypes might serve as a predictive biomarker to improve prognosis in patients with metastatic CRC treated with FOLFOX.

Factors Influencing Parental Compliance in Bringing Their Children to Undergo Chemotherapy at Dr. Cipto Mangunkusumo Hospital

Background: Cancer is a disease that can be treated with several therapies, including chemotherapy. Chemotherapy is a type of anti-cancer drug treatment that works by killing cancer cells. Currently, this medical treatment has been covered by the national health insurance which is managed by the government that aimed at providing assurance of social protection and welfare. Adherence to chemotherapy is one of the treatments that can improve the quality of life of children with cancer.
 Objectives: The aim of this study is to identify the factors influencing parental adherence to bring their child undergoing chemotherapy.
 Methods: The research method was quantitative, employing a descriptive correlation approach and a cross-sectional design. The data was collected using a questionnaire. The sample was 96 parents of children who underwent chemotherapy, which taken by accidental sampling. Chi-square, Kendall's Tau B, and Kendall's Tau C were used in the analysis.
 Results: There was a significant relationship between education level (p value = 0.006), knowledge (p value = 0.003), and no relationship with work (p value = 0.291), economic status (p value = 0.269), distance (p value = 0.389), side effect (p value = 0.624), and support system (p value = 0.309) with the adherence of parents in bringing their children to chemotherapy.
 Conclusion: Health professionals can monitor and encourage parents to always bring their children to chemotherapy.

RLR-mediated IFN signaling and aberrant activation

Interferon (IFN) signaling is important for host cells in defending microorganisms. “Self” and “non-self” recognition is the key step for proper IFN functioning. Pathogen-derived double-stranded RNAs (dsRNAs) are immunogenic to the cytosolic sensor, RIG-I and MDA5. Together known as RIG-I-like receptors (RLRs), they form filament along the length of dsRNA substrate which in turn activate downstream cascades. Despite RLRs themselves and host encoded regulators managing to avoid self-intolerance, extensive studies in recent years uncovered that the boundary of “self” and “non-self” can be vague. Retrotransposon elements embedded in the genome of humans can turn into RLR ligands under certain circumstances, like incorrect RNA metabolism or epigenetic drug treatment, which in turn, lead to IFN signaling activation. The consequences of such activation can be different according to different circumstances. Here, we summarized the biological features of RLR-mediated IFN signaling and discussed aberrant IFN signaling through RLRs, including situations of gene mutations, irradiation, and anti-cancer drug treatment. We speculated that combining current cancer therapy and RLR-mediated IFN signaling activation would bring beneficial effects to cancer treatment.

Verification of the Usefulness of an Assessment and Risk Control Sheet that Promotes Management of Cancer Drug Therapy.

Background: Proper management of adverse events is crucial for the safe and effective implementation of anticancer drug treatment. Showa University Hospital uses our interview sheet (assessment and risk control [ARC] sheet) for the accurate evaluation of adverse events. On the day of anticancer drug treatment, a nurse conducts a face-to-face interview. As a feature of the ARC sheet, by separately describing the symptoms the day before treatment and the day of treatment and sharing the information on the medical record, it is possible to clearly determine the status of adverse events. In this study, we hypothesized that the usefulness and points for improvement of the ARC sheet would be clarified by using and evaluating a patient questionnaire. Methods: This study included 174 patients (144 at Showa University Hospital (Hatanodai Hospital) and 30 at Showa University Koto Toyosu Hospital (Toyosu Hospital) who underwent pre-examination interviews by nurses and received cancer chemotherapy at the outpatient center of Hatanodai and Toyosu Hospital. In the questionnaire survey, the ARC sheet’s content and quality, respondents’ satisfaction, structural strengths, and points for improvement were evaluated on a five-point scale. Results: The patient questionnaire received responses from 160 participants, including the ARC sheet use group (132 people) and the non-use group (28 people). Unlike the ARC sheet non-use group, the ARC sheet use group recognized that the sheet was useful to understand the adverse events of aphthous ulcers (p = 0.017) and dysgeusia (p = 0.006). In the satisfaction survey questionnaire, there was a high sense of security in the pre-examination interviews by nurses using the ARC sheet. Conclusions: The ARC sheet is considered an effective tool for comprehensively evaluating adverse events. Pre-examination interviews by nurses using ARC sheets accurately determined the adverse events experienced by patients with anxiety and tension due to confrontation with physicians.

Lysosome-targeting red fluorescent probe for broad carboxylesterases detection in breast cancer cells

Available online The abnormal carboxylesterase (CES) expression is closely related to many diseases such as hyperlipidemia, atherosclerosis, obesity, liver cancer, type 2 diabetes mellitus and gastrointestinal stromal tumors. The detection of a single enzyme in practical samples is often constrained by the structural diversity of CESs. Thus, the development of broad-carboxylesterase responsive fluorescent probe, which can detect the presence of wide variety of CESs, may provide overall or category information from another point of view, supplementing the deficiency of single detection for CES subspecies. Organelle lysosome is involved in various cell processes, such as cell signaling, apoptosis, secretion, and energy metabolism. Up to date, lysosome-targeted fluorescent probes, especially those with red emission (over 550 nm, with relatively low biological harmfulness), for CES detection are still rare. A lysosomes-targeted red fluorescent probe CES-Lyso was designed to monitor intracellular a variety of carboxylesterases alteration with wonderful selectivity and sensitivity, which was further applied to distinguish different derived breast cancer cells and monitor carboxylesterase activity in the anticancer drug treatment.

A Simple LC-MS/MS Method for the Quantification of PDA-66 in Human Plasma.

The treatment of cancer is one of the most important pharmacotherapeutic challenges. To this end, chemotherapy has for some time been complemented by targeted therapies against specific structures. PDA-66, a structural analogue of the inhibitor of serine–threonine kinase glycogen synthase kinase 3β SB216763, has shown preclinical antitumour effects in various cell lines, with the key pathways of its anticancer activity being cell cycle modulation, DNA replication and p53 signalling. For the monitoring of anticancer drug treatment in the context of therapeutic drug monitoring, the determination of plasma concentrations is essential, for which an LC-MS/MS method is particularly suitable. In the present study, a sensitive LC-MS/MS method for the quantification of the potential anticancer drug PDA-66 in human plasma with a lower limit of quantification of 2.5 nM is presented. The method was successfully validated and tested for the determination of PDA-66 in mouse plasma and sera.

Body Mass Index is related to short-term retinal worsening in type 2 diabetes mellitus patients treated with anticancer drugs.

In cancer patients with diabetes, anticancer drugs (ADs) may negatively affect the course of diabetes vascular complications. The short-term effects of ADs on type 2 diabetes (T2DM) retinopathy are poorly known. This study evaluated the short-term effects of different classes of ADs on diabetic retinopathy (DR) and clinical risk factors for retinal worsening (RW) in cancer patients affected by T2DM. Retrospective single-center study evaluating 168 patients with T2DM and cancer. The diagnosis of T2DM preceded those of cancer in all patients. We evaluated the retinal short-term effects within the six months after the first-line ADs treatment. After ADs, 6% of patients had a short-term RW. BMI is positively associated with the risk of RW (OR 1.45, 95% confidence interval: 1.1-1.9, P<0.005). Patients treated with alkylating agents and topoisomerase inhibitors have an increased risk of RW (P=0.049 and P=0.057, respectively) and a significantly higher HDL level (P<0.01). To our knowledge, this study is the first investigating the short-term impact of ADs on DR of T2DM patients. Moreover, we provide information arose from a real-world setting. As confirmed by other studies, these findings could help to identify patients at risk for short-term RW, who should be promptly referred to the ophthalmologist for the prevention of visual impairment.

Treatment of anticancer drugs in a real wastewater effluent using nanofiltration: A pilot scale study

Although anticancer drugs occur in the aquatic environment at trace concentration levels, these drugs might be of environmental concern due to their potent mechanism of action. Hence, new treatment technologies should be explored and, if necessary, conventional wastewater treatment plants (WWTPs) should be upgraded to avoid the release of these drugs into the aquatic environment.The effectiveness of nanofiltration to remove six anticancer drugs from wastewater effluents was assessed by installing a pilot unit with a Desal 5DK membrane at a domestic WWTP. Of the target anticancer drugs, only capecitabine, cyclophosphamide and ifosfamide were detected on the feed samples and thus, the removal efficiency was only evaluated for these drugs. Several 4-hour assays were conducted to explore the conditions that would maximize the rejection of the detected compounds and minimize fouling. Rejections higher than 96% were obtained in all the experiments for the detected compounds, independently of the operating conditions tested. Working under a controlled transmembrane pressure of 6 bar and recovery rate of 73% minimized fouling. A 24-hour assay was then conducted under these conditions and a minimal decay on permeability was observed. Samples were collected over time and rejections higher than 94% were obtained for all the detected drugs. None of the samples induced a significant immobilization effect in Daphnia Magna after 48 h of exposure.

A Genome-Wide Association Study Predicts the Onset of Dysgeusia Due to Anti-cancer Drug Treatment.

Dysgeusia is a major side effect of anti-cancer drug treatment. Since dysgeusia significantly lowers the patient's QOL, predicting and avoiding its onset in advance is desirable. Accordingly, aims of the present study were to use a genome-wide association study (GWAS) to identify genes associated with the development of dysgeusia in patients taking anti-cancer drugs and to predict the development of dysgeusia using associated single nucleotide polymorphisms (SNPs). GWAS was conducted on 76 patients admitted to the Department of Hematology, Tokushima University Hospital. Using Sanger sequencing for 23 separately collected validation samples, the top two SNPs associated with the development of dysgeusia were determined. GWAS identified rs73049478 and rs41396146 SNPs on the retinoic acid receptor beta (RARB) gene associated with dysgeusia development due to the administration of anti-cancer drugs. Evaluation of the two SNPs using 23 validation samples indicated that the accuracy rate of rs73049478 was relatively high (87.0%). Thus, the findings of the present study suggest that the rs73049478 SNP of RARB can be used to predict the onset of dysgeusia caused by the administration of anti-cancer drugs.

The regulation of BNP transcription and DNA methylation modification in anticancer drug-induced cardiomyocyte toxicity.

Background) Genomic DNA, which contains all of the genetic information, is damaged by a variety of endogenous and environmental factors such as genotoxic chemicals, ionizing radiation and UV light. Consequently, the DNA repair process is constantly active as it responds to damage in the DNA structure. Not only cardiotoxicity of anticancer drug treatment but also ischemic heart disease and heart failure associated with overloaded pressure interfere with DNA damage response and DNA repair regulation in cardiomyocytes. We have reported that anticancer drug treatment causes a transient decrease in plasma brain natriuretic peptide (BNP) levels, but the mechanism of this decrease is unknown. In the present study, to clarify this molecular mechanism, we analyzed mouse hearts treated with anticancer drugs. Methods) C57BL/6 mice were treated with cisplatin (16 mg/kg, ip), and then BNP gene expression and DNA methylation in the heart were examined. Results) In cisplatin-treated mice, there was a transient decrease in BNP gene expression and an increase in DNA methylation of the BNP promoter region. Furthermore, DNA methyltransferase type 1 (DNMT1) was found to affect this DNA methylation. Conclusions) In cisplatin-treated mice, cardiac BNP transcription was repressed by DNA methylation. DNMT1 was suggested to be involved in this DNA methylation modification.