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• W4303684705 abstract "We evaluated the usefulness of an oncolytic virus (Suratadenoturev; OBP-301) against radioresistant oral squamous cell carcinoma. We confirmed the expression of human telomerase reverse transcriptase and the coxsackievirus and adenovirus receptor in cell lines. Also, we examined the potential presence in a patient who has received existing therapy that is amenable to treatment with OBP-301. We evaluated: (1) the antitumor effects of OBP-301 alone and in combination with radiotherapy on radioresistant cell lines, (2) the molecular mechanism underlying the radiosensitizing effect and cell death increased by the combination therapy, and (3) the antitumor effect of the combination therapy in vivo using xenograft models (a radioresistant cell line-derived xenograft in mouse and a patient-derived xenograft). Human telomerase reverse transcriptase and the coxsackievirus and adenovirus receptor were expressed in all cell lines. OBP-301 decreased the proliferative activity of these cell lines in a concentration-dependent manner, and significantly enhanced the antitumor effect of irradiation. Phosphorylated STAT3 and its downstream molecules, which correlated with apoptosis and autophagy, showed significant changes in expression after treatment with OBP-301. The combination therapy exerted a significant antitumor effect versus radiotherapy alone in both xenograft models. Combination of OBP-301 with radiotherapy exerts a synergistic effect and may represent a promising treatment for radioresistant oral squamous cell carcinoma. We evaluated the usefulness of an oncolytic virus (Suratadenoturev; OBP-301) against radioresistant oral squamous cell carcinoma. We confirmed the expression of human telomerase reverse transcriptase and the coxsackievirus and adenovirus receptor in cell lines. Also, we examined the potential presence in a patient who has received existing therapy that is amenable to treatment with OBP-301. We evaluated: (1) the antitumor effects of OBP-301 alone and in combination with radiotherapy on radioresistant cell lines, (2) the molecular mechanism underlying the radiosensitizing effect and cell death increased by the combination therapy, and (3) the antitumor effect of the combination therapy in vivo using xenograft models (a radioresistant cell line-derived xenograft in mouse and a patient-derived xenograft). Human telomerase reverse transcriptase and the coxsackievirus and adenovirus receptor were expressed in all cell lines. OBP-301 decreased the proliferative activity of these cell lines in a concentration-dependent manner, and significantly enhanced the antitumor effect of irradiation. Phosphorylated STAT3 and its downstream molecules, which correlated with apoptosis and autophagy, showed significant changes in expression after treatment with OBP-301. The combination therapy exerted a significant antitumor effect versus radiotherapy alone in both xenograft models. Combination of OBP-301 with radiotherapy exerts a synergistic effect and may represent a promising treatment for radioresistant oral squamous cell carcinoma. Oral squamous cell carcinoma (OSCC) is one of the most common types of cancer of the oral cavity. However, the survival rate has not improved despite advancements in diagnostic modalities and treatments.1Siegel R.L. Miller K.D. Fuchs H.E. Jemal A. Cancer statistics, 2021.CA Cancer J. Clin. 2021; 71: 7-33Crossref PubMed Scopus (7572) Google Scholar Thus, the prognosis of advanced OSCC remains poor, with a 5-year survival rate of approximately 50%.2Barnes L. Eveson J.W. Sidransky D. Reichart P. Pathology and Genetics of Head and Neck Tumours. IARC, 2015Google Scholar This stagnation in the survival rate is mainly attributed to the existence of high-grade malignant cells that display important hallmarks of cancer, such as resistance to chemotherapy or radiotherapy, abnormal proliferation, and invasion or metastasis.3Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (41855) Google Scholar Among them, radioresistance is a serious problem that prevents improvement in treatment outcomes of radiotherapy, an important treatment option in OSCC.4Yamamoto V.N. Thylur D.S. Bauschard M. Schmale I. Sinha U.K. Overcoming radioresistance in head and neck squamous cell carcinoma.Oral Oncol. 2016; 63: 44-51Crossref PubMed Scopus (29) Google Scholar Recently, we established clinically relevant radioresistant (CRR) cell lines by irradiating cells with >60 Gy for 5 weeks at 2 Gy per day, as in actual clinical practice.5Kuwahara Y. Mori M. Oikawa T. Shimura T. Ohtake Y. Mori S. Ohkubo Y. Fukumoto M. The modified high-density survival assay is the useful tool to predict the effectiveness of fractionated radiation exposure.J. Radiat. Res. 2010; 51: 297-302Crossref PubMed Scopus (26) Google Scholar Based on preclinical research that used the CRR cell lines to investigate the molecular mechanism involved in radioresistance,6Fukumoto M. Clinically relevant radioresistant cell line: a simple model to understand cancer radioresistance.Med. Mol. Morphol. 2017; 50: 195-204Crossref PubMed Scopus (29) Google Scholar these cell lines are regarded as a good experimental resource. In Japan, 60% of patients age ≥70 years are newly diagnosed with cancer.7Hori M. Matsuda T. Shibata A. Katanoda K. Sobue T. Nishimoto H. Japan Cancer Surveillance Research GroupCancer incidence and incidence rates in Japan in 2009: a study of 32 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project.Jpn. J. Clin. Oncol. 2015; 45: 884-891Crossref PubMed Scopus (426) Google Scholar According to the guidelines established by the National Center for Biotechnology Information, the standard therapy for OSCC is composed of radical therapy with extensive resection of tumors and postoperative concurrent chemoradiotherapy (CRT).8NCCN Clinical Practice GuidelinesOlder Adult Oncologyhttp://www.nccn.org/professionals/physician_gls/f_guidelines.aspGoogle Scholar However, since old age is associated with a poorer reserve force, the application of this regimen in elderly patients with advanced OSCC is difficult. Of note, many of these patients are undergoing radiotherapy. Therefore, there is an urgent need for new approaches to overcome treatment resistance and to provide new treatment options for patients with OSCC. OBP-301 is a telomerase-specific tumor-lysing adenovirus developed by Fujiwara et al.9Kawashima T. Kagawa S. Kobayashi N. Shirakiya Y. Umeoka T. Teraishi F. Taki M. Kyo S. Tanaka N. Fujiwara T. Telomerase-specific replication-selective virotherapy for human cancer.Clin. Cancer Res. 2004; 10: 285-292Crossref PubMed Scopus (188) Google Scholar It infects target cells via its receptor, coxsackievirus and adenovirus receptor (CAR), whose expression correlates with the infection efficacy of the adenovirus.10Li D. Duan L. Freimuth P. O’Malley Jr., B.W. Variability of adenovirus receptor density influences gene transfer efficiency and therapeutic response in head and neck cancer.Clin. Cancer Res. 1999; 5: 4175-4181PubMed Google Scholar Following incorporation into the host DNA, OBP-301 produces adenoviral E1A and E1B in response to the promoter activity of human telomerase reverse transcriptase (hTERT). Its activity is related to that of telomeres, which are structural proteins at the ends of chromosomes that protect the DNA.10Li D. Duan L. Freimuth P. O’Malley Jr., B.W. Variability of adenovirus receptor density influences gene transfer efficiency and therapeutic response in head and neck cancer.Clin. Cancer Res. 1999; 5: 4175-4181PubMed Google Scholar,11Nakayama J. Tahara H. Tahara E. Saito M. Ito K. Nakamura H. Nakanishi T. Tahara E. Ide T. Ishikawa F. Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas.Nat. Genet. 1998; 18: 65-68Crossref PubMed Scopus (585) Google Scholar Ultimately, OBP-301 causes cell death at relatively high rates in hTERT-positive cancer cells in an hTERT-expression-dependent manner. In contrast, the replication and cytotoxicity of the virus are significantly limited in normal somatic cells.9Kawashima T. Kagawa S. Kobayashi N. Shirakiya Y. Umeoka T. Teraishi F. Taki M. Kyo S. Tanaka N. Fujiwara T. Telomerase-specific replication-selective virotherapy for human cancer.Clin. Cancer Res. 2004; 10: 285-292Crossref PubMed Scopus (188) Google Scholar,12Hashimoto Y. Watanabe Y. Shirakiya Y. Uno F. Kagawa S. Kawamura H. Nagai K. Tanaka N. Kumon H. Urata Y. Fujiwara T. Establishment of biological and pharmacokinetic assays of telomerase-specific replication-selective adenovirus.Cancer Sci. 2008; 99: 385-390Crossref PubMed Scopus (51) Google Scholar Preclinical research has demonstrated the antitumor effects of OBP-301 in numerous malignancies.9Kawashima T. Kagawa S. Kobayashi N. Shirakiya Y. Umeoka T. Teraishi F. Taki M. Kyo S. Tanaka N. Fujiwara T. Telomerase-specific replication-selective virotherapy for human cancer.Clin. Cancer Res. 2004; 10: 285-292Crossref PubMed Scopus (188) Google Scholar,12Hashimoto Y. Watanabe Y. Shirakiya Y. Uno F. Kagawa S. Kawamura H. Nagai K. Tanaka N. Kumon H. Urata Y. Fujiwara T. Establishment of biological and pharmacokinetic assays of telomerase-specific replication-selective adenovirus.Cancer Sci. 2008; 99: 385-390Crossref PubMed Scopus (51) Google Scholar, 13Liu D. Kojima T. Ouchi M. Kuroda S. Watanabe Y. Hashimoto Y. Onimatsu H. Urata Y. Fujiwara T. Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer.Mol. Cancer Ther. 2009; 8: 980-987Crossref PubMed Scopus (44) Google Scholar, 14Tanimoto T. Tazawa H. Ieda T. Nouso H. Tani M. Oyama T. Urata Y. Kagawa S. Noda T. Fujiwara T. Elimination of MYCN-amplified neuroblastoma cells by telomerase-targeted oncolytic virus via MYCN suppression.Mol. Ther. Oncol. 2020; 18: 14-23Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar In phase I clinical trials in the United States, OBP-301 has shown an efficacious and safe profile against several types of solid tumors.15Nemunaitis J. Tong A.W. Nemunaitis M. Senzer N. Phadke A.P. Bedell C. Adams N. Zhang Y.A. Maples P.B. Chen S. et al.A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors.Mol. Ther. 2010; 18: 429-434Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar Furthermore, it has been reported that monotherapy and radiation therapy can be used in combination to further improve the antitumor effect.16Shirakawa Y. Tazawa H. Tanabe S. Kanaya N. Noma K. Koujima T. Kashima H. Kato T. Kuroda S. Kikuchi S. et al.Phase I dose-escalation study of endoscopic intratumoral injection of OBP-301 (Telomelysin) with radiotherapy in oesophageal cancer patients unfit for standard treatments.Eur. J. Cancer. 2021; 153: 98-108Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar In head and neck squamous cell carcinoma (HNSCC), including OSCC, several studies evaluated mainly the antitumor effects of single-agent administration.17Fujita K. Kimura M. Kondo N. Sakakibara A. Sano D. Ishiguro Y. Tsukuda M. Anti-tumor effects of telomelysin for head and neck squamous cell carcinoma.Oncol. Rep. 2008; 20: 1363-1368PubMed Google Scholar, 18Kurihara Y. Watanabe Y. Onimatsu H. Kojima T. Shirota T. Hatori M. Liu D. Kyo S. Mizuguchi H. Urata Y. et al.Telomerase-specific virotheranostics for human head and neck cancer.Clin. Cancer Res. 2009; 15: 2335-2343Crossref PubMed Scopus (28) Google Scholar, 19Sakakibara A. Tsukuda M. Kondo N. Ishiguro Y. Kimura M. Fujita K. Takahashi H. Matsuda H. Examination of the optimal condition on the in vitro sensitivity to telomelysin in head and neck cancer cell lines.Auris Nasus Larynx. 2011; 38: 589-599Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Some studies reported the combined effects of treatment with anticancer drugs and radiation in vitro and in vivo.17Fujita K. Kimura M. Kondo N. Sakakibara A. Sano D. Ishiguro Y. Tsukuda M. Anti-tumor effects of telomelysin for head and neck squamous cell carcinoma.Oncol. Rep. 2008; 20: 1363-1368PubMed Google Scholar,20Kondo N. Tsukuda M. Kimura M. Fujita K. Sakakibara A. Takahashi H. Ishiguro Y. Toth G. Matsuda H. Antitumor effects of telomelysin in combination with paclitaxel or cisplatin on head and neck squamous cell carcinoma.Oncol. Rep. 2010; 23: 355-363Crossref PubMed Scopus (28) Google Scholar, 21Kuroda S. Fujiwara T. Shirakawa Y. Yamasaki Y. Yano S. Uno F. Tazawa H. Hashimoto Y. Watanabe Y. Noma K. et al.Telomerase-dependent oncolytic adenovirus sensitizes human cancer cells to ionizing radiation via inhibition of DNA repair machinery.Cancer Res. 2010; 70: 9339-9348Crossref PubMed Scopus (63) Google Scholar, 22Takahashi H. Hyakusoku H. Horii C. Takahashi M. Nishimura G. Taguchi T. Kondo N. Sakakibara A. Urata Y. Sano D. Telomerase-specific oncolytic adenovirus: antitumor effects on radiation-resistant head and neck squamous cell carcinoma cells.Head Neck. 2014; 36: 411-418Crossref PubMed Scopus (6) Google Scholar However, there are no reports examining the antitumor effect or mechanism underlying the development of resistance using radioresistant OSCC cell lines and a patient-derived xenograft (PDX) model. It is thought that radiation exerts its therapeutic effects on cancer cells by inducing various types of cell death (i.e., apoptosis, mitotic catastrophe, necrosis, and autophagy) and by inhibiting cell proliferation.23Baskar R. Lee K.A. Yeo R. Yeoh K.W. Cancer and radiation therapy: current advances and future directions.Int. J. Med. Sci. 2012; 9: 193-199Crossref PubMed Scopus (1107) Google Scholar Recently, our group reported that radiation-induced regulatory cell death can be classified into three categories, namely apoptosis, autophagy-dependent cell death, and necrosis.24Kuwahara Y. Tomita K. Urushihara Y. Sato T. Kurimasa A. Fukumoto M. Association between radiation-induced cell death and clinically relevant radioresistance.Histochem. Cell Biol. 2018; 150: 649-659Crossref PubMed Scopus (19) Google Scholar OBP-301 possesses strong antitumor activity that can lyse cancer cells by specifically proliferating in them.9Kawashima T. Kagawa S. Kobayashi N. Shirakiya Y. Umeoka T. Teraishi F. Taki M. Kyo S. Tanaka N. Fujiwara T. Telomerase-specific replication-selective virotherapy for human cancer.Clin. Cancer Res. 2004; 10: 285-292Crossref PubMed Scopus (188) Google Scholar Moreover, when OBP-301 is used in combination with existing treatment modalities, it can enhance the antitumor effects through various mechanisms, such as the DNA repair machinery, enhancing apoptosis, and local immune modification of tumors.22Takahashi H. Hyakusoku H. Horii C. Takahashi M. Nishimura G. Taguchi T. Kondo N. Sakakibara A. Urata Y. Sano D. Telomerase-specific oncolytic adenovirus: antitumor effects on radiation-resistant head and neck squamous cell carcinoma cells.Head Neck. 2014; 36: 411-418Crossref PubMed Scopus (6) Google Scholar,25Omori T. Tazawa H. Yamakawa Y. Osaki S. Hasei J. Sugiu K. Komatsubara T. Fujiwara T. Yoshida A. Kunisada T. et al.Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression.PLOS ONE. 2021; 16: e0250643Crossref PubMed Scopus (1) Google Scholar,26Kanaya N. Kuroda S. Kakiuchi Y. Kumon K. Tsumura T. Hashimoto M. Morihiro T. Kubota T. Aoyama K. Kikuchi S. et al.Immune modulation by telomerase-specific oncolytic adenovirus synergistically enhances antitumor efficacy with anti-PD1 antibody.Mol. Ther. 2020; 28: 794-804Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Several studies have identified radioresistance-related molecules using radioresistant OSCC cell lines. Reports in the past have focused on molecules identified by gene expression analyses to elucidate radioresistance mechanisms.27Lee S.Y. Park H.R. Cho N.H. Choi Y.P. Rha S.Y. Park S.W. Kim S.H. Identifying genes related to radiation resistance in oral squamous cell carcinoma cell lines.Int. J. Oral Maxillofac. Surg. 2013; 42: 169-176Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 28Ishigami T. Uzawa K. Higo M. Nomura H. Saito K. Kato Y. Nakashima D. Shiiba M. Bukawa H. Yokoe H. et al.Genes and molecular pathways related to radioresistance of oral squamous cell carcinoma cells.Int. J. Cancer. 2007; 120: 2262-2270Crossref PubMed Scopus (62) Google Scholar, 29M.W Y. Lin H.Y. Chiou W.Y. Lin R.I. Chen C.A. Lee M.S. Chi C.L. Chen L.C. Huang L.W. et al.IRAK2, an IL1R/TLR immune mediator, enhances radiosensitivity via modulating caspase 8/3-mediated apoptosis in oral squamous cell carcinoma.Front. Oncol. 2021; 11: 647175Crossref PubMed Scopus (4) Google Scholar However, few studies have been reported in OSCC with respect to mechanisms of radioresistance, particularly using multiple CRR cells established by the routine clinical irradiation of OSCC cell lines. In this study, we investigated in vitro and in vivo whether the combination of OBP-301 radiotherapy can overcome radioresistance in OSCC using a useful research model, namely CRR cells. We also investigated the mechanism of cell death induced by this combination in OSCC. In addition, we further validated the usefulness of this treatment in vivo, using a CRR cell-line-derived xenograft (CRR-CDX) model and the PDX model as a useful preclinical model. We analyzed the expression of CAR and hTERT, which have been reported as therapeutic target molecules of OBP-301,30Fujiwara T. Urata Y. Tanaka N. Telomerase-specific oncolytic virotherapy for human cancer with the hTERT promoter.Curr. Cancer Drug Targets. 2007; 7: 191-201Crossref PubMed Scopus (54) Google Scholar in OSCC cell lines and human normal oral keratinocytes (HNOKs) using real-time PCR and western blotting. Expression of CAR mRNA was detected in all cell lines, including HNOK (Figure 1A ). Expression of hTERT mRNA was confirmed in all OSCC cell lines, but not in HNOK (Figure 1A). In the western blotting analysis, although there was a difference in expression, CAR protein was detected in all cell lines (including HNOK). Expression of hTERT protein was detected in all OSCC cell lines, but not in HNOK (Figure 1B). To elucidate the clinical significance of hTERT in OSCC, we performed expression analysis of hTERT by immunohistochemical staining. In addition, we investigated the clinicopathological significance of hTERT in preoperative specimens obtained from 50 patients with advanced OSCC who underwent preoperative CRT. As shown in the representative images of immunohistochemical staining (Figure 1C), various hTERT expression patterns were confirmed in clinical OSCC. In the clinicopathological analysis, the high expression status of hTERT was significantly correlated with the clinical stage (p = 0.001), mode of invasion (p = 0.015), loco-regional recurrence (p = 0.023), and poor pathological response to CRT (p = 0.016) (Table 1). Moreover, 5-year disease-free survival (DFS) rates for patients with high hTERT expression were significantly lower than those for patients with low hTERT expression (p = 0.018) (Figure 1D, right). Furthermore, after adjusting for various clinicopathological factors, the influence of hTERT expression on DFS (hazard ratio, 3.241; 95% CI 1.112–9.992; p = 0.031) (Table 2) remained in the Cox proportional hazards regression model. On the other hand, although the 5-year overall survival (OS) rate tended to be lower in patients with low hTERT expression, the difference was not statistically significant (p = 0.420) (Figure 1D, left).Table 1Correlation between hTERT expression and clinicopathological factorsCharacteristicTotalhTERT expression (n = 50 cases)p valueHigh, n (%)Low, n (%)Age (years) Range40–8751–8140–87 ≤65155 (33.3)10 (66.7)0.948 >653512 (34.3)23 (65.7)Sex Male2810 (35.7)18 (64.3)0.773 Female227 (31.8)15 (68.2)cT category T2205 (25)15 (75)0.548 T3, T43012 (40)18(60)cN category N0147 (50)7 (50)0.136 ≥N13610 (27.8)26 (72.2)cStage III197 (36.8)12 (63.2)<0.001∗∗ IV3110 (32.3)21 (67.7)Differentiation Well-moderate113 (27.3)8 (72.7)0.594 Poor3914 (35.9)25 (64.1)Loco-regional recurrence Yes179 (52.9)8 (47.1)0.023∗ No337 (21.2)26 (78.8)Pathological response 0, I, IIa, IIb2513 (52)12 (48)0.007∗∗ III, IV254 (16)21 (84)Fisher’s exact test was used to examine the relationships between hTERT expression and clinicopathologic factors. OSCC, oral squamous cell carcinoma; cT, clinical T stage; cN, clinical N stage; cStgae, clinical Stage.∗p < 0.05 and ∗∗p < 0.01. Open table in a new tab Table 2Multivariate regression analysis results for predicting disease-free survival in 50 patients with OSCCVariableAssigned scoreHazard ratio (95% CI)p valueClinical T category T200.659 (0.195–2.278)0.502 T3, T41Clinical N category N000.880 (0.206–3.946)0.862 ≥N11Clinical stage III02.378 (0.727–9.258)0.157 IV1Differentiation Well-moderate01.222 (0.368–5.531)0.760 Poor1Worst pattern of invasion 1aBroad pushing margin., 2bBroad finger-like projections or separate large islands., 3cInvasive islands (>15 cells).02.908 (0.867–10.112)0.083 4dIslands of <5 cells, strands of tumor cells or single-cell infiltration., 5eTumor satellites separated from the main tumor interface by >1 mm.1Pathological response Grade 0, I, II01.114 (0.375–3.047)0.838 Grade ≥III1hTERT expression status High expression03.241 (1.112–9.992)0.031∗ Low expression1CI, confidence interval; OSCC, oral squamous cell carcinoma.∗p < 0.05.a Broad pushing margin.b Broad finger-like projections or separate large islands.c Invasive islands (>15 cells).d Islands of <5 cells, strands of tumor cells or single-cell infiltration.e Tumor satellites separated from the main tumor interface by >1 mm. Open table in a new tab Fisher’s exact test was used to examine the relationships between hTERT expression and clinicopathologic factors. OSCC, oral squamous cell carcinoma; cT, clinical T stage; cN, clinical N stage; cStgae, clinical Stage. ∗p < 0.05 and ∗∗p < 0.01. CI, confidence interval; OSCC, oral squamous cell carcinoma. ∗p < 0.05. To investigate whether OBP-301 contributed to the treatment of radiation-resistant OSCC, we analyzed the antitumor and radiosensitizing effects of OBP-301 on OSCC cells, including CRR cell lines. We first confirmed the antitumor effect of OBP-301 alone in OSCC cells. As shown in Figure 2A , treatment with OBP-301 exerted a concentration-dependent antitumor effect on OSCC cell lines (Figure 2A). Next, we explored the radiosensitizing effect of OBP-301 on OSCC cell lines, including CRR cells. The results of the modified high-density survival (MHDS) assay showed that OBP-301 had a significant radiosensitizing effect on OSCC cell lines, even CRR cells, compared with IR alone (Figures 2B and 2C). Calculation of the combination index demonstrated a synergistic antitumor effect of combination therapy in OSCC cell lines, including CRR cells (Figure 2D). We conducted a molecular biological study to elucidate the molecular mechanism underlying cell death caused by the combined use of OBP-301 and irradiation (IR). Apoptosis and autophagy are types of cell death induced after IR.24Kuwahara Y. Tomita K. Urushihara Y. Sato T. Kurimasa A. Fukumoto M. Association between radiation-induced cell death and clinically relevant radioresistance.Histochem. Cell Biol. 2018; 150: 649-659Crossref PubMed Scopus (19) Google Scholar Therefore, the effects of OBP-301 on apoptosis and autophagy were investigated. The results of an annexin-V assay showed that radiation-induced apoptosis was significantly increased following combination treatment with OBP-301 and IR versus OBP-301 or IR alone (Figure 3A ). In addition, the mitochondrial membrane potentials of the cell line irradiated after the administration of OBP-301 were significantly decreased versus those recorded after treatment with OBP-301 or IR alone (Figures 3B and 3C). Western blot analysis revealed a decrease in the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and its downstream molecule, B cell lymphoma extra large (Bcl-xL) in the OBP-301 and IR groups compared with the IR alone group. A decrease in p62 and an increase in the light chain 3-II (LC3-II)/light chain 3-I (LC3-I) ratio are considered markers of autophagy.31Pankiv S. Clausen T.H. Lamark T. Brech A. Bruun J.A. Outzen H. Øvervatn A. Bjørkøy G. Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy.J. Biol. Chem. 2007; 282: 24131-24145Abstract Full Text Full Text PDF PubMed Scopus (3268) Google Scholar In the present study, an increase in the LC3-II/LC3-I ratio and a decrease in p62 levels were observed in the OBP-301 and IR groups compared with the IR group. In addition, a slight increase in cleaved caspase 3 was observed in the OBP-301 and IR groups. Notably, significant changes in the expression of apoptosis/autophagy-related molecules that were not detected in the IR group were observed in the OBP-301 group (Figure 3D). In addition, changes in the expression of each molecule in the OBP-301 and IR groups were similar to those observed in the OBP-301 group. Furthermore, these phenomena were observed in two CRR cell lines, SAS-R and HSC-2-R. The therapeutic effects of OBP-301 combined with IR in vivo were determined using the OSCC-CDX and CRR-CDX models as shown in Figure 4A . In the OSCC-CDX model, PBS or BOP-301 alone failed to inhibit tumor growth; however, IR or OBP-301 combined with IR inhibited tumor growth. In addition, the combination of IR with OBP-301 significantly reduced tumor volume compared with IR or OBP-301 alone (Figure 4B). Furthermore, in the CRR-CDX model, an effect of OBP-301 and IR was observed compared with the OSCC-CDX model; however, the antitumor effect was decreased in the OBP-301 and IR alone groups at the end of the treatment schedule. Moreover, as observed in the OSCC-CDX model, IR plus OBP-301 exhibited the highest therapeutic effect (Figure 4C). In immunohistochemical analyses, the TdT-mediated dUTP-biotin nick-end labeling (TUNEL) assay showed a significant increase in apoptotic cells in the IR plus OBP-301 group (Figures 5A and 5C ), whereas autophagy was also significantly enhanced by immunohistochemical staining analysis as measured by a decrease in p62 expression (Figures 5B and 5D) in both models.Figure 5Analysis of apoptosis and autophagy in vivoShow full caption(A and B) The results in the OSCC-CDX model using SAS. (A, left) The number of apoptotic cells obtained from three independent experiments was calculated and statistically analyzed. The results are shown as means ± SD of three independent experiments; ∗∗p < 0.01. (A, right) Representative images of the TdT-mediated dUTP-biotin nick-end labeling (TUNEL) assay. Scale bars: 20 μm. (B, left) The number of autophagic cells obtained from three independent experiments was calculated and statistically analyzed. The results are shown as means ± SD of three independent experiments; ∗∗p < 0.01. (B, right) Representative images of p62 immunostaining. Scale bars: 20 μm. (C and D) The results in the CRR-CDX model using SAS-R. (C, left) The number of apoptotic cells obtained from three independent experiments was calculated and statistically analyzed. The results are shown as means ± SD of three independent experiments; ∗p < 0.05, ∗∗p < 0.01. (C, right) Representative images of the TUNEL assay. Scale bars: 20 μm. (D, left) The number of autophagic cells obtained from three independent experiments was calculated and statistically analyzed. The results are shown as means ± SD of three independent experiments; ∗∗p < 0.01. (D, right) Representative images of p62 immunostaining. Scale bars: 20 μm.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A and B) The results in the OSCC-CDX model using SAS. (A, left) The number of apoptotic cells obtained from three independent experiments was calculated and statistically analyzed. The results are shown as means ± SD of three independent experiments; ∗∗p < 0.01. (A, right) Representative images of the TdT-mediated dUTP-biotin nick-end labeling (TUNEL) assay. Scale bars: 20 μm. (B, left) The number of autophagic cells obtained from three independent experiments was calculated and statistically analyzed. The results are shown as means ± SD of three independent experiments; ∗∗p < 0.01. (B, right) Representative images of p62 immunostaining. Scale bars: 20 μm. (C and D) The results in the CRR-CDX model using SAS-R. (C, left) The number of apoptotic cells obtained from three independent experiments was calculated and statistically analyzed. The results are shown as means ± SD of three independent experiments; ∗p < 0.05, ∗∗p < 0.01. (C, right) Representative images of the TUNEL assay. Scale bars: 20 μm. (D, left) The number of autophagic cells obtained from three independent experiments was calculated and statistically analyzed. The results are shown as means ± SD of three independent experiments; ∗∗p < 0.01. (D, right) Representative images of p62 immunostaining. Scale bars: 20 μm. To evaluate the effects of combination therapy with OBP-301 and IR, we conducted experiments using a PDX model based on the schedule used in human clinical studies (Figure 6A ).16Shirakawa Y. Tazawa H. Tanabe S. Kanaya N. Noma K. Koujima T. Kashima H. Kato T. Kuroda S. Kikuchi S. et al.Phase I dose-escalation study of endoscopic intratumoral injection of OBP-301 (Telomelysin) with radiotherapy in oesophageal cancer patients unfit for standard treatments.Eur. J. Cancer. 2021; 153: 98-108Abstr" @default.
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• W4303684705 date "2022-12-01" @default.
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• W4303684705 title "An oncolytic virus as a promising candidate for the treatment of radioresistant oral squamous cell carcinoma" @default.
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• W4303684705 doi "https://doi.org/10.1016/j.omto.2022.10.001" @default.
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