Chemoresistance Factor Research Articles

Towards Imaging Pt Chemoresistance Using Gd(III)-Pt(II) Theranostic MR Contrast Agents.

Cisplatin and related Pt(II) chemotherapeutics are indispensable tools for the treatment of various solid tumors. Despite their widespread clinical use in approximately 50 % of chemotherapy regimens, they are hindered by issues with off-target toxicity and chemoresistance, both innate and acquired. To date, there is no effective way to predict the outcome of Pt(II) chemotherapy because the genes associated with resistance are not completely known or understood. Instead, patients undergo weeks to months of potentially harmful therapy before knowing if it is effective. Here we report two Gd(III)-Pt(II) theranostic MR contrast agents that contain cisplatin and carboplatin-based moieties respectively. We used these agents to demonstrate that accumulation differences in Pt(II) sensitive and resistant cells, a dominant factor in chemoresistance, can be imaged by MR. Both theranostic agents bind to DNA, are cytotoxic, and enhance the intracellular T1 -weighted MR contrast of multiple cell lines. Most importantly, the cisplatin-based agent accumulates less in Pt(II) resistant cells in vitro and in vivo, resulting in decreased MR contrast enhancement compared to the parent Pt(II) sensitive cell line. This straightforward method to image a key factor of Pt(II) resistance using MRI is an important first step towards the ultimate goals of predicting response to Pt(II) chemotherapy and monitoring for the onset of chemoresistance - a critical unmet need in medicine that could significantly improve patient outcomes.

Targeting Growth Factor Signaling Pathways in Pancreatic Cancer: Towards Inhibiting Chemoresistance.

Pancreatic cancer is one of the most deadly cancers, ranking amongst the top leading cause of cancer related deaths in developed countries. Features such as dense stroma microenvironment, abnormal signaling pathways, and genetic heterogeneity of the tumors contribute to its chemoresistant characteristics. Amongst these features, growth factors have been observed to play crucial roles in cancer cell survival, progression, and chemoresistance. Here we review the role of the individual growth factors in pancreatic cancer chemoresistance. Importantly, the interplay between the tumor microenvironment and chemoresistance is explored in the context of pivotal role played by growth factors. We further describe current and future potential therapeutic targeting of these factors.

Bufalin targets the SRC-3/MIF pathway in chemoresistant cells to regulate M2 macrophage polarization in colorectal cancer.

M2-polarized macrophages are one of critical factors in tumour chemoresistance. An increasing number of studies have shown that M2 macrophage polarization can be promoted by chemoresistance. A large number of evidences indicate that Bufalin has significant antitumour effect, previous studies have found that Bufalin can reduce the polarization of M2 macrophages to play an anti-tumour effect in vivo, but the mechanism remains unclear. In our study, we found that Bufalin reduced the polarization of M2 macrophages induced by chemoresistant cells both in vivo and in vitro; however, Bufalin had no obvious direct effect on M2 macrophage polarization. Furthermore, we demonstrated that Bufalin targeted the SRC-3 protein to reduce MIF release in chemoresistant cells in order to regulate the polarization of M2 macrophages. More interestingly, we also found that Cinobufacini, Bufalin is its main active monomer, which its could regulate the polarization of M2 macrophages to enhance the anti-tumour effect of oxaliplatin in vivo and in the clinic. Overall, this study provides a theoretical basis for the clinical application of drugs containing Bufalin as the main active ingredient in combination with established chemotherapy for the treatment of colorectal cancer.

AB052. SOH21AS116. Visceral fat as a tumour promotor: the role of adipose-derived factors in the immune-mediated chemoresistance of oesophageal adenocarcinoma

AB052. SOH21AS116. Visceral fat as a tumour promotor: the role of adipose-derived factors in the immune-mediated chemoresistance of oesophageal adenocarcinoma

CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3β axis.

Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance. Therefore, identifying causative factors for chemoresistance is of high importance. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma (OSCC) lines identified CMTM6 as a top-ranked upregulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy (CT) nonresponders as compared with CT responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma was observed from Kaplan-Meier plot analysis. Stable knockdown (KD) of CMTM6 restored cisplatin-mediated cell death in chemoresistant OSCC lines. Upon CMTM6 overexpression in CMTM6-KD lines, the cisplatin-resistant phenotype was rescued. The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatin-induced cell death and tumor burden substantially. The transcriptome analysis of CMTM6-KD and control chemoresistant cells depicted enrichment of the Wnt signaling pathway. We demonstrated that CMTM6 interaction with membrane-bound Enolase-1 stabilized its expression, leading to activation of Wnt signaling mediated by AKT–glycogen synthase kinase-3β. CMTM6 has been identified as a stabilizer of programmed cell death ligand 1. Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC.

Risk factors for chemoresistance in metastatic high-risk Gestational Trophoblastic Neoplasia

BACKGROUND: Gestational trophoblastic neoplasia (GTN) is a tumor known to be sensitive to chemotherapy. However, a subset of patients still develop resistance to the primary intensive chemotherapy. OBJECTIVE: This study aimed to determine the risk factors for multidrug resistance among high-risk metastatic GTN patients at University of the Philippines–Philippine General Hospital from January 2014 to December 2018. MATERIALS AND METHODS: A case–control study involving 111 high-risk metastatic GTN patients who underwent primary intensive chemotherapy Etoposide Methotrexate Actinomycin Cyclophosphamide Oncovin (EMACO) was done at the Philippine General Hospital from January 2014 to December 2018. The medical records of eligible patients were retrieved and reviewed. A comparison of the profile between patients who achieved remission (controls) and those who exhibited chemoresistance (cases) to the EMACO regimen was done. Stepwise logistic regression analysis and Cox's proportional hazards regression were used to determine the significant risk factors that could predict EMACO chemoresistance among these high-risk patients. RESULTS: The cases and controls were comparable in terms of their clinicodemographic profiles. Adjusting for confounders, multivariate analysis showed that the number of metastasis, FIGO stage, and World Health Organization (WHO) prognostic scores were all predictors of survival. Using the fitted logistic regression model, the accuracy of predicted death and survival was 85.16%. CONCLUSION: The pretreatment serum beta-human chorionic gonadotropin level, number of metastasis, tumor size, FIGO stage, and WHO prognostic score were significant predictors of treatment failure. A higher number of metastatic lesions, stage, and WHO prognostic scores indicated poor survival.

Distinct clinical and biological characteristics of acute myeloid leukemia with higher expression of long noncoding RNA KIAA0125

Expression of long non-coding RNA KIAA0125 has been incorporated in various gene expression signatures for prognostic prediction in acute myeloid leukemia (AML) patients, yet its functions and clinical significance remain unclear. This study aimed to investigate the clinical and biological characteristics of AML bearing different levels of KIAA0125. We profiled KIAA0125 expression levels in bone marrow cells from 347 de novo AML patients and found higher KIAA0125 expression was closely associated with RUNX1 mutation, but inversely correlated with t(8;21) and t(15;17) karyotypes. Among the 227 patients who received standard chemotherapy, those with higher KIAA0125 expression had a lower complete remission rate, shorter overall survival (OS) and disease-free survival (DFS) than those with lower expression. The prognostic significance was validated in both TCGA and GSE12417 cohorts. Subgroup analyses showed that higher KIAA0125 expression also predicted shorter DFS and OS in patients with normal karyotype or non-M3 AML. In multivariable analysis, higher KIAA0125 expression remained an adverse risk factor independent of age, WBC counts, karyotypes, and mutation patterns. Bioinformatics analyses revealed that higher KIAA0125 expression was associated with hematopoietic and leukemic stem cell signatures and ATP-binding cassette transporters, two predisposing factors for chemoresistance.

Overexpression of nuclear factor kappa B (NF-кB) protein as a risk factor for anthracyclin chemoresistance in luminal a subtype locally advanced breast cancer (LABC) at Sanglah General Hospital, Bali - Indonesia

Background: Around 68.6% of women who have breast cancer seek medical treatment at a locally advanced stage (LABC), where the neoadjuvant chemotherapy (NAC) modality is the initial choice therapy. Luminal A was recorded as the subtype with the chemotherapy response being the most resistant among others. The cause of chemoresistance is multi-factorial, and several studies correlate this condition with several anti-apoptotic agents expressed in the nucleus of cancer cells, especially nuclear factor-kappa B (NF-кB). The NF-κB transcription factor as an anti-apoptotic agent in some cancers blocks the apoptotic pathway through the extrinsic and intrinsic pathways. NF-κB plays a vital role in the development of chemoresistance. Understanding the NF-κB pathway and perceiving more about the cellular characteristics of LABC is very important to develop NF-κB inhibitors as therapy. NF-κB as a transcription factor can be considered a promising research target because it can affect oncogenes' transcription and play an essential role in prognostic and predictive biomarkers. This study was conducted to determine whether NF-κB overexpression is a risk factor for anthracycline-based neoadjuvant chemoresistance in Luminal A subtype LABC patients at Sanglah General Hospital.Methods: An unpaired case-control study was conducted at Sanglah General Hospital. The research subjects were 40 people, divided into case groups (chemoresistance) and control groups (chemosensitive). Hereafter the NF-κB H-Score was carried out by IHC examination. Data are presented in table form and analyzed by Chi-square test or Fischer exact.Results: Samples of cases with NF-κB overexpression were obtained 13 (65%), compared with the control group 7 (35%) (p<0.05). Multivariate analysis has shown that NF-κB overexpression is an independent factor against anthracycline-based chemotherapy resistance in advanced LABC patients with local luminal subtypes with p=0.013; OR 3.45 (95% CI=2.94-12.65).Conclusion: NF-κB expression in Luminal A subtype LABC can be used as a predictor for anthracycline-based neoadjuvant chemoresistance. NF-κB overexpression is a predictor factor for NAC chemoresistance in luminal A subtype LABC.

Abstract 4063: Design and development of a novel 5-FU modified siRNA against BCL2 with enhanced efficacy and the unique ability to be delivered vehicle free into cancer cells

Abstract Evasion of apoptosis is one of the major hallmarks of cancer and an important factor in chemoresistance. Thus, targeting apoptosis regulation is an important therapeutic approach. Anti-apoptotic BCL2, an oncogene and therapeutic target, is overexpressed in several different cancer types. There have been various approaches developed to target BCL2 including the FDA approved Venetoclax. In this study we have developed a modified siRNA against BCL2 that has enhanced efficacy and also can be delivered into cancer cells without any vehicle. We developed this siRNA by replacing uracil residues in the siRNA with 5-flurouracil (5-FU). This modification incorporates the effects of both 5-FU and siBCL2, to have an enhanced therapeutic effect. We tested several different modified siBCL2's, one with only the sense strand modified, one with only the antisense strand modified and one with both strands modified. We found the modified siBCL2 with both strands modified with 5-FU was most effective at inhibiting BCL2. Importantly, we were able to demonstrate via qRT-PCR and Western blot, that this modified siBCL2 retains its siRNA function and inhibits BCL2 expression in several different cancer types including colon cancer, lung cancer and lymphoma. In addition, in lymphoma cells, we found that our modified siBCL2 has better efficacy than BCL2 inhibitor Venetoclax. Finally, we were able to demonstrate that modified siBCL2 can be delivered into cancer cells without a delivery vehicle. This unique feature may be significant in overcoming the challenge of delivery, which remains a major obstacle for RNA therapeutics. This modified siBCL2 has therapeutic potential for several different cancers. Beyond BCL2, the modification approach we demonstrated may be applicable to other siRNAs and has potential as a platform technology for siRNA based therapeutics. Citation Format: Andrew Fesler, Ga-Ram Hwang, John Yuen, Jingfang Ju. Design and development of a novel 5-FU modified siRNA against BCL2 with enhanced efficacy and the unique ability to be delivered vehicle free into cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4063.

Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma.

Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive biomarkers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DDR1 is upregulated during chemotherapy both in vitro and in vivo. Moreover, analysis of a cohort of patients with LUAD suggested that high DDR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DDR1 inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD.

MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models.

Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal cancer marked by amplification of MDM2, an inhibitor of the tumor suppressor TP53. DDLPS patients with higher MDM2 amplification have lower chemotherapy sensitivity and worse outcome than patients with lower MDM2 amplification. We hypothesized that MDM2 amplification levels may be associated with changes in DDLPS metabolism. Six patient-derived DDLPS cell line models were subject to comprehensive metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling to assess associations with MDM2 amplification and their responses to metabolic perturbations. Comparing metabolomic profiles between MDM2 higher and lower amplification cells yielded a total of 17 differentially abundant metabolites across both panels (FDR < 0.05, log2 fold change < 0.75), including ceramides, glycosylated ceramides, and sphingomyelins. Disruption of lipid metabolism through statin administration resulted in a chemo-sensitive phenotype in MDM2 lower cell lines only, suggesting that lipid metabolism may be a large contributor to the more aggressive nature of MDM2 higher DDLPS tumors. This study is the first to provide comprehensive metabolomic and lipidomic characterization of DDLPS cell lines and provides evidence for MDM2-dependent differential molecular mechanisms that are critical factors in chemoresistance and could thus affect patient outcome.

Identification of cisplatin-resistant factor by integration of transcriptomic and proteomic data using head and neck carcinoma cell lines.

ABSTRACTCisplatin is an important drug for the treatment of head and neck squamous cell carcinoma (HNSCC). Determining chemoresistant factors prior to treatment will lead to great benefits for clinicians and patients. Here, we evaluated chemoresistant factors by integrating proteomic and transcriptomic data using HNSCC cell lines to identify a more precise chemoresistant factor in HNSCC. We used four HNSCC cell lines: cisplatin-sensitive, acquired cisplatin resistance, naturally cisplatin-resistant, and acquired 5-FU resistance. Proteomic analysis was performed using iTRAQ, tandem mass spectrometry, and liquid chromatography-electrospray ionization-tandem mass spectrometry. Transcriptomic analysis was performed using microarrays. By integrating these independent data, common factors were addressed and functional analysis was performed using small interfering RNAs (siRNAs) to change the chemosensitivity. Using iTRAQ analysis, 7 proteins were identified as specific for cisplatin chemoresistance factors. Transcriptomic analysis revealed hundreds of potential candidate factors. By combining and integrating these data, S100A2 was identified as a potential cisplatin-specific chemoresistance factor. Functional analysis with siRNA revealed that the expression of S100A2 was reduced and cisplatin sensitivity recovered in the acquired and naturally cisplatin-resistant cell lines, but not in the cisplatin-sensitive cell lines. S100A2 was identified as a cisplatin-specific chemoresistance factor by integrating the transcriptomic and proteomic results obtained using HNSCC cell lines. This is a novel technique that allows for a precise identification, also known as a comprehensive analysis. Our findings indicate that these proteins could be used as biomarkers of HNSCC treatments, providing physicians with new treatment strategies for patients with HNSCC, showing chemoresistance.

Cross‑validation of genes potentially associated with neoadjuvant chemotherapy and platinum‑based chemoresistance in epithelial ovarian carcinoma.

Ovarian carcinomas have the poorest prognosis and the highest mortality among gynecological malignancies. Neoadjuvant chemotherapy (NACT) is considered as a novel therapeutic strategy and an alternative treatment for advanced epithelial ovarian cancer (AEOC). The aim of the present study was to identify the core genes related to platinum-based NACT resistance in AEOC and to allow screening at the molecular level for the most appropriate ovarian cancer patients for NACT. We obtained three drug-resistant microarrays GSE114206, GSE41499 and GSE33482 from the Gene Expression Omnibus (GEO) database as well as a microarray representing NACT, GSE109934. Bioinformatics analysis revealed the nature of the four potential candidate genes for using in functional enrichment analyses and interaction network construction. The potential associations and possible genetic alterations among the DEGs were summarized using the STRING database in Cytoscape and the cBioPortal visualization tool, respectively. A total of 63 genes were identified as DEGs from GSE109934 representing NACT. From the drug-resistant GSE114206 and GSE41499 datasets, 106 DEGs containing 36 upregulated genes and 70 downregulated genes were selected, and from the drug-resistant GSE114206 and GSE33482 datasets, 406 DEGs with 157 upregulated genes and 249 downregulated genes were selected. The 36 upregulated DEGs and the 70 downregulated genes were notably abundant in the different categories. In KEGG pathway analysis, the 157 upregulated genes and the 249 downregulated genes were concentrated in distinctive signaling pathways. Four potential genes associated with NACT and platinum-based chemoresistance were screened, including nuclear factor of activated T-cells, cytoplasmic 1 (NAFTc1), Kruppel-like factor 4 (KLF4), nuclear receptor subfamily 4 group A member 3 (NR4A3) and hepatocyte growth factor (HGF). Our study showed that the mRNA expression levels of NAFTc1, NR4A3 and HGF were increased in drug-resistant OC cell lines (all P<0.01), whereas the mRNA expression levels of KLF4 were notably lower in the SKOV3-CDDP and HeyA8-CDDP cell line (all P<0.01) but higher in the A2780-CBP cell line. The NAFTc1, KLF4, NR4A3 and HGF genes may be potential therapeutic targets for NACT and platinum-based chemoresistance factors as well as candidate biomarkers in AEOC. Determination of the expression levels of these four genes in tumor tissues before planning NACT treatment or initial surgery would be beneficial for AEOC patients.

Identification of CCN1 transferred by extracellular vesicles derived from breast cancer cells responsible for doxorubicin-resistance.

e12623 Background: The anthracycline drug, doxorubicin, is one of the most frequently used chemotherapeutic drugs for breast cancer. However, not all patients respond to doxorubicin-containing combination chemotherapy due to chemo-resistance (natural or acquired). Preceding researches have shown that extracellular vesicles (EVs) can be readily harvested from peripheral blood for further biological analysis and thus perform an attractive source of tumor derived materials for identification of chemo-resistance factors. This study aims to provide a theoretical basis to use CCN1-containing EVs as new biomarkers and therapeutic targets for doxorubicin-resistance in breast cancer. Methods: A strategy combining RNA-sequencing technique and bioinformatic analysis was used to determine the level of differential expressed mRNAs in EVs samples from cellular supernatant (n = 4) and blood serum (n = 8) from chemo-resistant and chemo-sensitive patients. Serial gene expression analysis in patients (n = 203) who treated with neoadjuvant (GSE32603) were also employed to identified drug-resistance-related proteins. The expression of CCN1 was detected in doxorubicin-resistant cell lines (MCF-7/DOX),MCF-7 and their EVs by RT-qPCR and western blot. Then, we used cell apoptosis and immunofluorescence stain to confirm the ability of CCN1-containing EVs in conferring drug resistance. Immunohistochemistry stain and RT-qPCR were used to prove the expression level of CCN1 in tumor tissues from breast cancer patients (n = 80) and in serum EVs from patients treated with the whole neoadjuvant chemotherapy. Results: We combined the differentially expressed mRNAs from three datasets and found identified CCN1 as a drug-resistance-related factor in breast cancer. The expression level of CCN1 is much higher in MCF-7/DOX cells and their EVs compared with MCF-7 cells and their EVs. The addition of CCN1-containing EVs has been found significantly increase the resistance to doxorubicin in sensitive cells. Moreover, a higher expression level of CCN1 was detected in the progressive disease (PD)/stable disease (SD) group than in the partial response (PR)/complete response (CR) group both in tissues and serum EVs. Conclusions: All These findings demonstrate that CCN1-containing EVs appear to be essential in conferring resistance to doxorubicin. More importantly, we exhibit the potential applications of CCN1-containing EVs for predicting the efficiency and outcome of patients treated with doxorubicin-based chemotherapy.

Pretreatment thrombocytosis as an independent predictive factor for chemoresistance and poor survival in epithelial ovarian cancer

BackgroundThrombocytosis is related to tumor stage and survival in ovarian cancer in addition to the common complications of malignant diseases, such as anemia and inflammation. The aim of our study was to clarify the precise prognostic impact of pretreatment thrombocytosis in epithelial ovarian cancer.MethodsWe retrospectively analyzed 280 consecutive patients who were treated for epithelial ovarian cancer at our institution between 2001 and 2011.ResultsPretreatment thrombocytosis was observed in 18.9% of all patients and was associated with advanced FIGO stage, primary treatment, operation achievement, histologic subtype, microcytic hypochromic anemia (MHA), and nonmalignant inflammatory condition (P = 0.0018, 0.0028, 0.00050, 0.034, 0.00090 and 0.0022). In the patients who relapsed after primary adjuvant chemotherapy (n = 126), thrombocytosis was associated with a shorter treatment-free interval (TFI) (P = 0.0091). The univariate and multivariate analyses revealed that thrombocytosis was independently associated with TFI and MHA (P = 0.021 and 0.0091). Patients with thrombocytosis had worse progression-free survival (PFS) and overall survival (OS) than those without thrombocytosis (P < 0.0001 and < 0.0001). The multivariate analyses for prognostic factors demonstrated that thrombocytosis was significant for poor PFS and OS (P = 0.0050 and 0.022) independent of stage, histology, primary treatment, operation achievement, nonmalignant inflammatory condition and MHA.ConclusionsThe current findings indicate that the detrimental survival impact of pretreatment thrombocytosis in epithelial ovarian cancer may be independent of tumor extent but rather attributed to chemoresistance, further supporting the therapeutic potential of targeting thrombopoietic cytokines in the disease.

Chemoresistance-associated alternative splicing signatures in serous ovarian cancer.

Primary platinum-based chemoresistance occurs in ~30% of patients with serous ovarian cancer. Chemoresistance is the main cause of disease recurrence, and accurate predictors to identify these patients with chemoresistance are required. Alternative splicing (AS) is a post-transcriptional modification process that is altered in cancer. A possible association between AS and chemoresistance is unclear and needs to be studied comprehensively in ovarian cancer. In the present study, RNA-sequencing data and clinical information for 320 patients with ovarian serous cystadenocarcinoma (OV) were downloaded from The Cancer Genome Atlas (TCGA) database. Splicing events were determined using the TCGA SpliceSeq tool. Seven types of AS events were identified. Univariate and multivariate logistic analyses were performed, and predictive models for OV chemoresistance were established, as well as a splicing network. A total of 22,036 AS events were identified in 7,404 genes, with 915 AS events detected in 677 genes that were significantly associated with chemoresistance in patients with OV. A receiver operating characteristic (ROC) curve was constructed for resistance predictive models composed of the most significant AS events. The area under the ROC curve was 0.931, indicating strong and efficient prediction of chemoresistance. Additionally, the high-risk score was associated with shorter overall survival. The splicing correlation network suggested a potential role of splicing factors in chemoresistance. In summary, the present study created a powerful predictor for primary platinum-based chemoresistance in patients with OV, identified splicing networks that could be involved in potential mechanisms of chemoresistance and provided potential targets to overcome chemoresistance.

Targeting Doublecortin‐like Kinase 1 (DCLK1) in Colon Cancer: An In‐silico Approach

Cancer stem cells (CSCs) are proposed to be a contributing factor in colorectal cancer (CRC) recurrence and chemo‐resistance, as a result of increased expression of ABC transporters and their innate ability to self‐renew and enter a quiescent state. Current standard therapies are ineffective at eliminating these CSC populations, hence there is a need to identify novel agents to effectively inhibit their growth. Multiple surface markers have been identified for CRC‐CSCs, though few have shown promise as a clinical target. Recently, doublecortin‐like kinase 1 (DCLK1) was established as a CSC marker in CRC and pancreatic cancers. The N‐terminal doublecortin domains(DCX) bind microtubules and regulate their polymerization, while the C‐terminal serine/threonine‐protein kinase domain is involved in cellular signaling. DCLK1 is a marker of Tuft cells in normal intestinal crypts, but in cancer is found to be highly expressed in CSC populations that play a critical role in tumor progression, based on lineage tracing experiments. Specific ablation of DCLK1+ stem cells causes marked regression of polyps without apparent damage to the normal intestine, distinguishing DCLK1 as a CSC marker. Recently, marmelin, a phytochemical from Aegle marmelos, has been shown to target DCLK1 and reduce CRC tumor growth in vivo. Hence, DCLK1 represents an attractive target for CSC‐targeted drug discovery. The present study is aimed to identify small molecule inhibitors of DCLK by using in silico molecular docking‐based screening. For this, we tested a library of FDA‐approved drugs and kinase inhibitors using Autodock Vina software. Compounds were assessed on their ability to bind within the ligand binding site of the C‐terminal kinase domain. The compounds are ranked‐based on their binding energies and hydrogen bonding patterns.Support or Funding InformationThe Olathe North MSOE Center for BioMolecular Modeling SMART Team used 3‐D modeling and printing technology to examine the structure‐function relationship in this project.

Clinical Significance of Jagged-1 Activated by APEX1 as a Chemoresistance Factor in Advanced Gastric Cancer.

We investigated the clinical role of the molecular targets, APEX1 and Jagged-1, and the Apex1 - Jagged-1 cascade in gastric cancer cells. We used 6 human gastric cancer cell lines (SNU-1, SNU-5, SNU-16, NCI-N87, KATO- III and AGS), and demonstrated the chemosensitivity of APEX1 and Jagged-1 through the MTT assay and immunoblotting. Tumor growth was assayed following cisplatin and 5-FU treatment using a xenograft model injected with KATO-III cells. Moreover, gastric tumor samples from 9 patients, divided in 2 groups according to chemotherapy response, were examined by immunocytochemical (IHC) staining, and protein expression levels were scored. Following APEX1 knockdown, the MTT assay revealed that the IC50 of cisplatin and 5-FU in AGS cells was decreased approximately 7% and 15%, respectively, however, their decrease in chemoresistant KATO-III cells was decreased by approximately 21% and 67% for cisplatin and 5-FU, respectively. The tumor volume of KATO-III/sicontrol mice treated with cisplatin and 5-FU was affected less, compared with KATO-III/siAPEX1 mice treated with cisplatin and 5-FU. Also, the expression levels of APEX1, Jagged-1 and CD133, assayed by IHC staining, were higher in the chemorefractory group than in the chemoresponsive group. Jagged-1-activated signaling by APEX1 plays a role in advanced gastric cancer.

Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment.

Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy. Herein, we sought to determine the efficacy of phosphoinositide 3-kinase (PI3K)/Akt inhibition using three AZD compounds in a NOD-SCID xenograft mouse model and Akt regulation in a panel of eight ovarian cancer cell lines. Elevated Akt phosphorylation on Ser473 but not on Thr308 in cancerous tissues correlated with short progression-free survival (PFS), overall survival (OS), and death. AZD8835 and AZD8186 inhibited Akt phosphorylation while AZD5363 augmented its phosphorylation on Ser473. To add, all compounds inhibited the Akt downstream effectors 4E-BP1 and p70S6 kinase. AZD8835 and AZD5363 sensitized chemoresistant ovarian cancer cells to cisplatin and paclitaxel treatment. Only AZD5363 could inhibit COL11A1 mRNA and promoter activity, which are important factors in Akt regulation and chemoresistance in ovarian cancer. By using a mouse xenograft model, AZD8835 and AZD5363, but not AZD8186, caused a significant reduction in tumor formation. AZD compounds did not change the mRNA expression of BRCA1/BRCA in ovarian cancer cells, but AZD8835 inhibited BRCA1/BRCA2 mRNA expression and p-ERK protein expression in OVCAR-8 cells with the KRAS mutation. This study highlights the importance of PI3K/Akt in ovarian tumor progression and chemoresistance and the potential application of AZD compounds, especially AZD8835 and AZD5363, as therapeutic agents for the treatment of ovarian cancer.

The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity

Platinum-based agents, such as cisplatin, form the mainstay of currently used chemotherapeutic regimens for several malignancies; however, the main limitations are chemoresistance and ototoxic side effects. In this study we used two different polyphenols, curcumin and ferulic acid as adjuvant chemotherapeutics evaluating (1) in vivo their antioxidant effects in protecting against cisplatin ototoxicity and (2) in vitro the transcription factors involved in tumor progression and cisplatin resistance. We reported that both polyphenols show antioxidant and oto-protective activity in the cochlea by up-regulating Nrf-2/HO-1 pathway and downregulating p53 phosphorylation. However, only curcumin is able to influence inflammatory pathways counteracting NF-κB activation. In human cancer cells, curcumin converts the anti-oxidant effect into a pro-oxidant and anti-inflammatory one. Curcumin exerts permissive and chemosensitive properties by targeting the cisplatin chemoresistant factors Nrf-2, NF-κB and STAT-3 phosphorylation. Ferulic acid shows a biphasic response: it is pro-oxidant at lower concentrations and anti-oxidant at higher concentrations promoting chemoresistance. Thus, polyphenols, mainly curcumin, targeting ROS-modulated pathways may be a promising tool for cancer therapy. Thanks to their biphasic activity of antioxidant in normal cells undergoing stressful conditions and pro-oxidant in cancer cells, these polyphenols probably engage an interplay among the key factors Nrf-2, NF-κB, STAT-3 and p53.