miR-145-5p and miR-203a-5p overcome imatinib resistance in myelogenous leukemic cells through metabolic reprogramming-Supplemenntary data

Imatinib is the most effective therapy for chronic myeloid leukemia (CML), but many patients eventually develop resistance to it after an initial satisfactory response. This study investigated the potential of three miRNAs (miR-106b-5p, miR-145-5p, miR-203a-5p) in overcoming imatinib resistance in leukemic cells. The imatinib-resistant K562 (IR-K562) cells were developed and transfected with one of the three miRNAs to evaluate their potency in overcoming imatinib resistance. The changes in the metabolic profile were studied using flux balance analysis (FBA) and the data was validated using qRT-PCR.Among the three miRNAs, the ectopic expression of either miR-145-5p or miR-203a-5p was able to sensitize the IR-K562 cells to imatinib. The concentration of key oncometabolites; glucose, lactate, and glutamine, in the culture media of the miR-transfected IR-K562 cells, reverted to the same levels as seen in imatinib-sensitive K562 cells. In addition, the FBA analysis revealed that the metabolism of lipid, fatty acids, and electron transport chain were significantly altered in resistant cells. The FBA data was also validated at the molecular level. Interestingly, the imatinib treatment coupled with the transfection of miR-145-5p or miR-203a-5p cells could reverse the metabolic flux of IR-K562 to the levels seen in imatinib-sensitive K562 cells. This study highlights the key metabolic changes that occur during development of imatinib resistance. It also identifies the specific miRNAs which can be targeted to overcome imatinib resistance in CML.

miR-145-5p and miR-203a-5p overcome imatinib resistance in myelogenous leukemic cells through metabolic reprogramming

Imatinib is the most effective therapy for chronic myeloid leukemia (CML), but many patients eventually develop resistance to it after an initial satisfactory response. This study investigated the potential of three miRNAs (miR-106b-5p, miR-145-5p, miR-203a-5p) in overcoming imatinib resistance in leukemic cells. The imatinib-resistant K562 (IR-K562) cells were developed and transfected with one of the three miRNAs to evaluate their potency in overcoming imatinib resistance. The changes in the metabolic profile were studied using flux balance analysis (FBA) and the data was validated using qRT-PCR.Among the three miRNAs, the ectopic expression of either miR-145-5p or miR-203a-5p was able to sensitize the IR-K562 cells to imatinib. The concentration of key oncometabolites; glucose, lactate, and glutamine, in the culture media of the miR-transfected IR-K562 cells, reverted to the same levels as seen in imatinib-sensitive K562 cells. In addition, the FBA analysis revealed that the metabolism of lipid, fatty acids, and electron transport chain were significantly altered in resistant cells. The FBA data was also validated at the molecular level. Interestingly, the imatinib treatment coupled with the transfection of miR-145-5p or miR-203a-5p cells could reverse the metabolic flux of IR-K562 to the levels seen in imatinib-sensitive K562 cells. This study highlights the key metabolic changes that occur during development of imatinib resistance. It also identifies the specific miRNAs which can be targeted to overcome imatinib resistance in CML.

Concurrent silencing of TBCE and drug delivery to overcome platinum-based resistance in liver cancer

Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma (HCC). Herein, RNAseq analysis revealed that elevated tubulin folding cofactor E (TBCE) expression is associated with platinum-based chemotherapy resistance. High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients. Mechanistically, TBCE silencing significantly affects cytoskeleton rearrangement, which in turn increases cisplatin-induced cycle arrest and apoptosis. To develop these findings into potential therapeutic drugs, endosomal pH-responsive nanoparticles (NPs) were developed to simultaneously encapsulate TBCE siRNA and cisplatin (DDP) to reverse this phenomena. NPs (siTBCE + DDP) concurrently silenced TBCE expression, increased cell sensitivity to platinum treatment, and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft (PDX) models. Taken together, NP-mediated delivery and the co-treatment of siTBCE + DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.

GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma / 医学前沿

Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.

Tertiary Prevention of Ovarian Cancer After PARP Inhibitor Therapy / 肿瘤防治研究

The tertiary prevention approaches of ovarian cancer include whole-person care, training of the patients to cooperate with physicians in the periods of treatment and follow-up, training program of the qualified surgeons, and recognition of biological behavior changes of relapse after PARPi therapy. Surgery remains the cornerstone in the management of ovarian cancer, but the role of surgery after PARPi remains unknown. Recently, the US FDA withdrew the indication of three PARP inhibitors in the treatment of recurrent ovarian cancer with ≥3 lines of chemotherapy because of their ≥30% increased death risk. Thus, we should pay more attention to the biological recurrence and chemoresistance caused by PARP inhibitors and post-progression survival in ovarian cancer.

Hydroxysafflor yellow A inhibits proliferation, migration, and chemoresistance of colorectal cancer cells through Akt/mTOR-autophagy pathway / 中国中药杂志

In recent years, the clinical treatment of colorectal cancer(CRC) has made great progress, but chemoresistance is still one of the main reasons for reducing the survival rate of patients with colorectal cancer. Therefore, ameliorating chemotherapy resis-tance is an urgent problem to be solved. The purpose of this study was to investigate the regulatory role and related molecular mechanisms of hydroxysafflor yellow A(HSYA) in colorectal cancer cell proliferation, migration, and 5-fluorouracil(5-FU) chemoresistance. In this study, HCT116 and HT-29 cells were used as research subjects. Firstly, methyl thiazolyl tetrazolium(MTT) assay and colony formation assay were used to detect and analyze the effect of HSYA on the proliferation of CRC cells. Secondly, the effect of HSYA on the cell cycle in CRC cells was analyzed by cell cycle assay. Furthermore, the effect of HSYA on the migration of CRC cells was analyzed by wound-healing assay and Transwell assay. Based on the above, the influences of HSYA on 5-FU chemoresistance of CRC cells and related molecular mechanisms were explored and analyzed. The results showed that HSYA significantly inhibited the proliferation and migration of CRC cells, and arrested the cell cycle in G_0/G_1 phase. In addition, HSYA significantly ameliorated the chemoresistance of CRC cells to 5-FU. The results of acridine orange staining and Western blot showed that the autophagy activity of CRC cells in the HSYA and 5-FU combined treatment group was significantly higher than that in the 5-FU single drug treatment group. As compared with the 5-FU single drug treatment group, the phosphorylation levels of protein kinase B(Akt) and mammalian target of rapamycin(mTOR) in the HSYA and 5-FU combined treatment group were significantly reduced, indicating that the Akt/mTOR signaling pathway in the combined treatment group was down-regulated in CRC cells. In conclusion, HSYA may upregulate autophagy activity through the Akt/mTOR signaling pathway, thereby inhibiting the proliferation and migration of CRC cells and ameliorating the chemoresistance to 5-FU.

Emerging roles of Aurora-A kinase in cancer therapy resistance

Aurora kinase A (Aurora-A), a serine/threonine kinase, plays a pivotal role in various cellular processes, including mitotic entry, centrosome maturation and spindle formation. Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer, including lung cancer, colorectal cancer, and breast cancer. Alteration of Aurora-A impacts multiple cancer hallmarks, especially, immortalization, energy metabolism, immune escape and cell death resistance which are involved in cancer progression and resistance. This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance, including chemoresistance (taxanes, cisplatin, cyclophosphamide), targeted therapy resistance (osimertinib, imatinib, sorafenib, etc.), endocrine therapy resistance (tamoxifen, fulvestrant) and radioresistance. Specifically, the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair, feedback activation bypass pathways, resistance to apoptosis, necroptosis and autophagy, metastasis, and stemness. Noticeably, our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1, ARID1A and MYC gene mutation tumors, and potential synergistic strategy for mTOR, PAK1, MDM2, MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase. In addition, we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.

Estrategias terapéuticas actuales en el tratamiento del cáncer de ovario

Introducción: El cáncer de ovario es uno de los tumores más frecuentes y letales entre las mujeres. Esto se debe a su detección en estados tardíos y al desarrollo de quimiorresistencia a la terapia estándar. El desarrollo de terapias dirigidas contra las propiedades distintivas de las células cancerosas y sus características habilitadoras ha surgido como una alternativa promisoria para el tratamiento de estos tumores. Objetivo: Describir las actuales estrategias terapéuticas dirigidas contra las distintas capacidades de las células tumorales en el tratamiento del cáncer de ovario. Método: Se realizó una búsqueda en las bases de datos ScienceDirect, Redalyc, Latindex, ResearchGate, PubMed, Elsevier, ClinicalTrials.gov, SpringerLink, LARVOL´s CLIN, Registro Público Cubano de Ensayos Clínicos, entre enero y abril de 2023. Se seleccionaron 50 artículos referentes al cáncer de ovario y las alternativas para su tratamiento. Desarrollo: Se mencionaron los diversos factores que influyen en la elección de terapias contra el cáncer de ovario. Se describieron las actuales dianas terapéuticas utilizadas en el tratamiento de esta neoplasia, así como el empleo de múltiples fármacos aprobados y en fases de estudio, y las combinaciones sinérgicas de los mismos. Consideraciones finales: Actualmente existen disímiles opciones de tratamiento del cáncer de ovario. A pesar de que la eficacia clínica de los agentes dirigidos todavía está restringida a subtipos moleculares específicos y ningún ensayo ilustra un beneficio en la supervivencia general, son notorios los resultados alcanzados en el desarrollo de fármacos específicamente dirigidos contra la inestabilidad del genoma y angiogénesis sostenida.

Introduction: Ovarian cancer is one of the most common and lethal tumor in women. This happens as a result of late-stage cancer detention and an increased chemoresistance to standard therapy. The current development in therapies to kill the cancer cells and its spread tendencies has emerged as a key alternative to treat tumors. Objective: To describe the current therapeutic strategies lead to confront different capabilities of tumor cells found in the ovarian cancer treatment. Method: A search of literuture was carried out in the following databases ScienceDirect, Redalyc, Latindex, ResearchGate, PubMed, Elsevier, ClinicalTrials.gov, SpringerLink, LARVOL's CLIN, Cuban Public Registry of Clinical Trials, from January to April 2023. A total of 50 text concerning ovarian cancer subject and alternative for treatment were selected. Development: The driving factors that promoted the use of ovarian cancer therapies were pointed out. The current therapeutic targets used in the treatment of this neoplasia were described, as well as the use of multiple approved drugs or in process of approval, including the synergistic drug combinations. Final considerations: There are a lot of options currently being implemented in ovarian cancer treatment. Despite clinical efficacy of targeted therapy, it´s presented still restricted to specific molecular subtypes and none of the assays illustrated survival benefit in general; the results obtained in the process of drugs development specifically targeting genome instability and sustained angiogenesis have been remarkable.

Introdução: O câncer de ovário é um dos tumores mais frequentes e letais entre as mulheres. Isso se deve à sua detecção em estágios tardios e ao desenvolvimento de quimiorresistência à terapia padrão. O desenvolvimento de terapias direcionadas contra as propriedades distintas das células cancerígenas e suas características facilitadoras surgiu como uma alternativa promissora para o tratamento desses tumores. Objetivo: Descrever as atuais estratégias terapêuticas dirigidas contra as diferentes capacidades das células tumorais no tratamento do câncer de ovário. Método: Foi realizada uma busca nas bases de dados ScienceDirect, Redalyc, Latindex, ResearchGate, PubMed, Elsevier, ClinicalTrials.gov, SpringerLink, LARVOL's CLIN, Registro Público Cubano de Ensaios Clínicos, entre janeiro e abril de 2023. 50 artigos referentes ao câncer de ovário e as alternativas para o seu tratamento. Desenvolvimento: Foram mencionados os vários fatores que influenciam a escolha das terapias contra o câncer de ovário. Foram descritos os atuais alvos terapêuticos utilizados no tratamento desta neoplasia, bem como o uso de múltiplas drogas aprovadas e em fase de estudo, e suas combinações sinérgicas. Considerações finais: Atualmente existem opções de tratamento dissimilares para o câncer de ovário. Apesar de a eficácia clínica dos agentes direcionados ainda estar restrita a subtipos moleculares específicos e nenhum ensaio mostrar benefício na sobrevida global, são notáveis os resultados alcançados no desenvolvimento de fármacos direcionados especificamente contra a instabilidade do genoma e a angiogênese sustentada.

Study on the mechanism of kinesin family proteins 2C in chemotherapy resistance of ovarian cancer / 中华老年医学杂志

Objective:To investigate the role of kinesin family proteins(KIF)2C in chemoresistance of epithelial ovarian cancer and its potential molecular mechanism.Methods:The differential expression of KIF2C in cisplatin-sensitive cell line A2780 and cisplatin-resistant cell line A2780DDP was detected.Different concentrations and time of cisplatin were added to A2780 cell line to detect the differential expression of KIF2C.The ovarian cancer cell line KIF2C-OV with stable overexpression of KIF2C was constructed by lentivirus infection of A2780DDP cell line.The same concentration of cisplatin was added to KIF2C-OV and its control group(Ctrl-OV)cell lines.The effect of KIF2C overexpression on the proliferation of drug-resistant cell line A2780DDP was detected by Cell Counting Kit-8(CCK-8). Finally, the molecular mechanism of KIF2C resistance in ovarian cancer cell lines was preliminarily explored.Results:KIF2C was significantly down-regulated in A2780DDP cells.After cisplatin was added to A2780 cell line, the expression of KIF2C decreased with the increase of cisplatin concentration and action time.The ovarian cancer cell line KIF2C-OV with stable overexpression of KIF2C was constructed by lentivirus infection of A2780DDP cell line.After adding cisplatin, the proliferation ability of KIF2C-OV cell line was significantly lower than that of Ctrl-OV cell line.The expression of p-Erk was increased in A2780DDP cell line.The expression of p-Erk in A2780 cell line was increased with the increase of cisplatin concentration and time.After overexpression of KIF2C in A2780DDP ovarian cancer cell line, the expression level of p-Erk decreased.Conclusions:KIF2C may be a potential target gene of chemotherapy resistance in ovarian cancer, which may play its role through MAPK/ERK pathway.

Evaluation and simplification of risk factors in FIGO 2000 scoring system for gestational trophoblastic neoplasia: a 19-year retrospective analysis / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

OBJECTIVES@#The International Federation of Gynecology and Obstetrics (FIGO) 2000 scoring system classifies gestational trophoblastic neoplasia (GTN) patients into low- and high-risk groups, so that single- or multi-agent chemotherapy can be administered accordingly. However, a number of FIGO-defined low-risk patients still exhibit resistance to single-agent regimens, and the risk factors currently adopted in the FIGO scoring system possess inequable values for predicting single-agent chemoresistance. The purpose of this study is therefore to evaluate the efficacy of risk factors in predicting single-agent chemoresistance and explore the feasibility of simplifying the FIGO 2000 scoring system for GTN.@*METHODS@#The clinical data of 578 GTN patients who received chemotherapy between January 2000 and December 2018 were retrospectively reviewed. Univariate and multivariate logistic regression analyses were carried out to identify risk factors associated with single-agent chemoresistance in low-risk GTN patients. Then, simplified models were built and compared with the original FIGO 2000 scoring system.@*RESULTS@#Among the eight FIGO risk factors, the univariate and multivariate analyses identified that pretreatment serum human chorionic gonadotropin (hCG) level and interval from antecedent pregnancy were consistently independent predictors for both first-line and subsequent single-agent chemoresistance. The simplified model with two independent factors showed a better performance in predicting single-agent chemoresistance than the model with the other four non-independent factors. However, the addition of other co-factors did improve the efficiency. Overall, simplified models can achieve favorable performance, but the original FIGO 2000 prognostic system still features the highest discrimination.@*CONCLUSIONS@#Pretreatment serum hCG level and interval from antecedent pregnancy were independent predictors for both first-line and subsequent single-agent chemoresistance, and they had greater weight than other non-independent factors in predicting single-agent chemoresistance. The simplified model composed of certain selected factors is a promising alternative to the original FIGO 2000 prognostic system, and it shows comparable performance.

Mechanism of miR-155 Promoting Drug Resistance in Childhood Acute Lymphoblastic Leukemia by Regulating Wnt/β-Catenin Signaling Pathway / 中国实验血液学杂志

OBJECTIVE@#To investigate the mechanism of miR-155 promoting drug resistance of children B-ALL to Ara-C by regulating Wnt/β-Catenin signaling pathway.@*METHODS@#The expression of miR-155 in bone marrow tissue and cell line of B-ALL was detected by PCR. The chemotherapy resistant strain REH/ Ara-C was constructed by using REH cells. REH/ Ara-C cells were transfected with miR-155 inhibitor. The proliferation of REH/Ara-C cells was detected by EdU. The apoptosis of REH/ Ara-C cells was detected by flow cytometry. The drug resistance of REH/Ara-C cells were analyzed by CCK-8 method and colony formation assay. The expression of Wnt/β-Catenin signaling pathway related proteins were determined by Western blot. MiR-155 inhibitor and Wnt activator agonist were used to transfect REH/Ara-C cells, and their effects on cell proliferation, apoptosis and drug resistance were determined.@*RESULTS@#Compared with normal tissues and cells, the expression level of miR-155 in B-ALL bone marrow tissue/cell line was increased (P<0.05); Compared with drug sensitive B-ALL tissues/cell lines, the expression level of miR-155 in drug resistant B-ALL tissues and cell lines was increased (P<0.05); Inhibition of miR-155 expression decreased the proliferation of REH/Ara-C cells (P<0.05), promoted apoptosis (P<0.05), enhanced the cytotoxicity of Ara-C (P<0.05), and inhibited Wnt/β-Catenin signaling pathway related protein and MDR1 gene expression (P<0.05), which could be reversed by activating Wnt expression (P<0.05).@*CONCLUSION@#The expression of miR-155 is up-regulated in bone marrow of children with B-ALL, which may be related to the activation of Wnt/β-Catenin signaling pathway promotes the proliferation of B-ALL cells and inhibits apoptosis, which leads to chemotherapy resistance.

Third‑line chemotherapy after resistance to Etoposide, Cisplatin‑ Etoposide, Methotrexate, Actinomycin (EP‑EMA) in high risk gestational trophoblastic neoplasia: Experience at the Philippine General Hospital / Philippine Journal of Obstetrics and Gynecology

Objective@#To describe the experience of the Division of Trophoblastic Diseases of the Philippine General Hospital with the various third‑line chemotherapeutic regimens among high‑risk gestational trophoblastic neoplasia (GTN) patients who experienced resistance after receiving the etoposide, cisplatin–etoposide, methotrexate, actinomycin (EP‑EMA) regimen@*Materials and Methods@#This was a 17‑year descriptive study that included all patients who used various salvage chemotherapy after resistance to EP‑EMA as treatment for metastatic, high‑risk GTN at the Philippine General Hospital from January 2002 to December 2018. The medical records of eligible patients were retrieved and assessed. All abstracted data were analyzed retrospectively. Descriptive statistics were used to compute for percentages for the various demographic characteristics of the sample population@*Results@#From January 2002 to December 2018, a total of 291 patients with metastatic, high‑risk gestational GTN were treated at the Philippine General Hospital. Of these, only seven patients received various third‑line chemotherapy regimens after resistance to EP‑EMA. One patient was excluded due to incomplete data. Among the third‑line chemotherapeutic regimens used, 3 patients received paclitaxel/carboplatin, two of whom went into remission while one expired. One patient had vincristine, bleomycin, and cisplatin (VBP) with two adjunctive surgeries in the form of hysterectomy and thoracotomy. She also went into remission. Two patients received paclitaxel–cisplatin/paclitaxeletoposide (TP/TE) as third line of treatment. The first was shifted back to EP‑EMA and eventually developed chemoresistance to EP‑EMA and had multiple toxicities. After multidisciplinary conference with the patient and family, they decided to go home and refused further chemotherapy. The other patient had TP/TE followed by bleomycin–etoposide–cisplatin, with adjunctive hysterectomy. Despite multiple cycles of chemotherapy, the disease persisted. She was offered palliative care and the family decided to bring her home. Both patients eventually expired at home@*Conclusion@#No conclusion can be made about the most effective third line chemotherapy for resistant high‑risk GTN because of the limited cases included in this study. An individualized approach is still recommended. Physicians and centers for patients caring for such patients are encouraged to report their experience to improve the management of future patients

Effect of miR-33a-3p on Chemoresistance of Colorectal Cancer by Regulating EphA2 / 华中科技大学学报(医学版)

@#Objective Toinvestigatetheregulatoryeffect of microRNA-33a-3p(miR-33a-3p)on chemoresistances of colorectal cancer(CRC). Methods Theexpression of miR-33a-3pin CRC parentalcells(HCT8)and drug-resistantcelllines(HCT8/5-Fu and HCT8/DDP) was detected by quantitative real-time PCR. The miR-33a-3p mimics and negative control mimics were constructed andtransfectedinto CRCdrug-resistantcells. Cell proliferation,apoptosis,cellcycledistributionandchemosensitivity weretested. Thetarget genes of miR-33a-3p were predicted via bioinformatics methods,andtheeffect of overexpressed miR- 33a-3p onthe downstreamtarget gene EphA2 was detected by quantitative real-time PCR and Western blot. Results The expression of miR-33a-3pin HCT8/5-Fu and HCT8/DDP cells was significantlylowerthanthat ofthe parentalcells(P <0.01) .Compared with the negative control group,overexpression of miR-33a-3p could suppress HCT8/5-Fu and HCT8/DDP cells proliferation and promotecell apoptosis,and block cells cyclein G2/M phase as well as enhancecell chemosensitivity(P <0.05) .Bioinformatics predictionresults showedthat EphA2 might bea downstreamtarget gene of miR-33a-3p,andits expression was significantlyreducedin HCT8/5-Fu and HCT8/DDP cells transfected with miR-33a-3p mimics. Conclusion The miR-33a-3p mayreversethechemoresistance of CRC byregulatingthe expressionlevel of downstreamtarget gene EphA2.

Capilliposide from Lysimachia capillipes promotes terminal differentiations and reverses paclitaxel resistance in A2780T cells of human ovarian cancer by regulating Fos/Jun pathway / 中草药·英文版

Objective: To investigate the potential effect of Lysimachia capillipes capilliposide (LCC) on the chemo sensitivity and the stemness of human ovarian cancer cells. Methods: Cell Counting Kit-8 (CCK8) was used to measure the IC

Phosphorylation of Cofilin-1 Enhances Paclitaxel Resistance of Epithelial Ovarian Cancer Cells by Inhibiting Apoptosis / 生物医学与环境科学（英文）

Objective@#To investigate the molecular mechanism of high phosphorylation levels of cofilin-1 (p-CFL-1) associated with paclitaxel resistance in epithelial ovarian cancer (EOC) cells.@*Methods@#Cells displaying varying levels of p-CFL-1 and CFL-1 were created by plasmid transfection and shRNA interference. Cell inhibition rate indicating paclitaxel efficacy was assessed by Cell Counting Kit-8 (CCK-8) assay. Apoptosis was assessed by flow cytometry and protein levels were detected by western blotting. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of phosphokinases and phosphatases of CFL-1. Survival analysis evaluated the correlation between the prognosis of EOC patients and the levels of p-CFL-1 and slingshot-1 (SSH-1).@*Results@#High levels of p-CFL-1 were observed in EOC cells that survived treatment with high doses of paclitaxel. SKOV3 cell mutants with upregulated p-CFL-1 showed impaired paclitaxel efficacy, as well as decreased apoptosis rates and pro-survival patterns of apoptosis-specific protein expression. Cytoplasmic accumulation of p-CFL-1 inhibited paclitaxel-induced mitochondrial apoptosis. SSH-1 silencing mediated CFL-1 phosphorylation in paclitaxel-resistant SKOV3 cells. Clinically, the high level of p-CFL-1 and the low level of SSH-1 in EOC tissues were closely related to chemotherapy resistance and poor prognosis in EOC patients.@*Conclusion@#The SSH-1/p-CFL-1 signaling pathway mediates paclitaxel resistance by apoptosis inhibition in EOC and is expected to be a potential prognostic predictor.

Factors affecting remission to salvage chemotherapy with EtoposideCisplatin/Etoposide-MethotrexateActinomycin D (EP-EMA regimen) among chemoresistant high-risk Gestational Trophoblastic Neoplasia patients admitted in a tertiary institution: A 10-year retrospective descriptive study / Philippine Journal of Obstetrics and Gynecology

Background@#Approximately 20%–25% of high-risk gestational trophoblastic neoplasia (GTN) patients initially treated with first-line chemotherapy regimen develop resistance to the regimen. The EP-EMA (Etoposide-cisplatin and etoposide, methotrexate and actinomycin D) regimen is the most commonly utilized second-line agent. @*Objective@#This study aimed to identify factors leading to remission using etoposide and cisplatin-etoposide, methotrexate, and Actinomycin D (EP-EMA) as salvage chemotherapy among resistant high-risk GTN.@*Methods@#This is a retrospective descriptive study that reviewed the medical records of patients admitted in the section of trophoblastic diseases diagnosed with high-risk GTN from January 2006 to December 2015. @*Results@#The medical records of 20 patients were retrieved and reviewed. The complete remission rate with EP-EMA is 60% (12/20). The overall survival rate for 1 year is 70% (14/20). Only 20% of the patients went home against advice and did not complete treatment. This regimen reported toxicities ranging from Grade 2–4 myelosuppression and electrolyte imbalance. Forty-five percent had Grade 4 neutropenia and Grade 2 anemia and 20% had Grade 2 thrombocytopenia. Hypokalemia and hypomagnesemia were noted in 8 patients (40%). Although not statistically significant, a trend showed that those in the remission group mostly had Stage III diseases with metastasis only in the lungs, prognostic score of between 7 and 12, and with beta-human chorionic gonadotropin (β-hCG) levels <10,000 mIu/ml at the start of EP-EMA treatment.@*Conclusion@#There is an improved response with EP-EMA chemotherapy across the years in our institution. Factors such as stage of disease, pulmonary metastasis, and low β-hCG at the start EP-EMA chemotherapy denote a possible good response and may contribute to patients' complete remission with EP-EMA chemotherapy. However, further studies with larger patient sample size are recommended to support the latter.

8-Azaguanine-induced autophagy contributes to its chemoresistance in hepatic cancer cells / 药学学报

Autophagy, an evolutionarily conserved process by which components of the cell are degraded in lysosomes, may facilitate survival of cancer cells under stress conditions. 8-Azaguanine (8-AG), an inhibitor of purine nucleotide biosynthesis, shows antineoplastic activity in multiple tumor cells. However, chemoresistance has restricted its development as an anticancer agent, and the mechanism of 8-AG resistance is not fully understood. We report here that 8-AG induces a protective autophagy to eliminate its cytotoxicity, and inhibition of autophagy increases cellular sensitivity of cancer cells to 8-AG treatment. Using HepG2 or SMMC-7721 hepatic cancer cell lines, we found that 8-AG inhibited cell viability and induced intrinsic apoptosis, accompanied by the up-regulation of the pro-apoptotic protein BimS, one of Bim (also known as BCL-2-like protein 11, BCL2L11) isoforms. Furthermore, 8-AG treatment enhanced the autophagy flux by promoting the dephosphorylation and activation of Unc-51-like autophagy activating kinase 1 (ULK1) via Akt/mTORC1 (mammalian target of rapamycin complex 1) signaling inhibition. Depletion of autophagy-related gene 7 (ATG7) markedly enhanced the level of BimS, and promoted cell death in response to 8-AG. 8-AG in combination with autophagy inhibitor chloroquine (CQ) or bafilomycin A1 (Baf A1) promoted the 8-AG-induced apoptosis in hepatic cancer cells. Altogether, these findings suggest that autophagy promotes chemoresistance of cancer cells for 8-AG, and blocking autophagy increases cellular sensitivity of cancer cells to 8-AG treatment.

Downregulation of hsa_circ_0000936 sensitizes resistant glioma cells to temozolomide by sponging miR-1294

Glioma is one of the most aggressive forms of brain tumor and is hallmarked by high rate of mortality,metastasis and drug resistance. Herein, we explore the role of circular RNA (circRNA) hsa_circ_0000936 inthe resistance of glioma cells to temozolomide (TMZ). In this study, Relative changes in gene expression levelswere compared using qRT-PCR. The role of hsa_circ_0000936 was characterized by cell count kit -8 assay andflow cytometry. Luciferase reporter assay was carried out for target validation.We found that hsa_circ_0000936was upregulated in glioma tissues as compared to their adjacent normal tissues. Increased expression ofhsa_circ_0000936 was found in the glioma tissues of patients showing resistance to TMZ compared with thatof patients showing sensitivity to TMZ. The upregulation of hsa_circ_0000936 was also confirmed in TMZresistant glioma cells. miR-1294 was downregulated in TMZ-resistant glioma cells and identified as a directtarget of hsa_circ_0000936. Downregulation of hsa_circ_0000936 increased the sensitivity of TMZ-resistantglioma cells towards TMZ. Moreover, restoration of miR-1294 could abrogate the promoting effect ofhsa_circ_0000936 on TMZ resistance in TMZ-resistant glioma cells. In conclusion, downregulation ofhsa_circ_0000936 sensitizes TMZ-resistant glioma cells to TMZ by sponging miR-1294, suggesting thathsa_circ_0000936 may be a potential target for overcoming the resistance of glioma cells to TMZ.

Mecanismos moleculares emergentes y células madre leucémicas en la quimiorresistencia de tumores hematológicos / Emerging molecular mechanisms and leukemic stem cells in chemoresistance of hematologic tumors

Resumen Las leucemias agudas son trastornos clonales originados a partir de células hematopoyéticas primitivas multipotenciales que se caracterizan por la proliferación, diferenciación y maduración aberrante de células progenitoras leucémicas como resultado de varios eventos genéticos y epigenéticos. Aunque en la actualidad se han implementado diferentes esquemas de quimioterapia para mejorar el pronóstico de los pacientes, las leucemias agudas representan una malignidad hematológica con pobre desenlace clínico y bajas tasas de supervivencia en pacientes pediátricos y adultos Colombianos. Uno de los principales obstáculos para el tratamiento exitoso del cáncer es el desarrollo de resistencia a los medicamentos durante la quimioterapia y la enfermedad recurrente. En el estudio de la biología de las células tumorales, se reconoce que los diversos cambios oncogénicos y la evolución clonal que sufren las células tumorales, son cambios biológicos que les confieren mecanismos de resistencia a la quimioterapia convencional, que a su vez se traducen en un incremento en las tasas de mortalidad y/o el aumento de recaídas en los pacientes que padecen esta enfermedad. Por lo tanto, el estudio de los mecanismos empleados por las células leucémicas para escapar del efecto citotóxico del tratamiento empleado para combatir la enfermedad es un objetivo primordial de la investigación en cáncer. En este contexto, el objetivo del presente artículo es hacer una revisión detallada de los avances más recientes en la comprensión de los mecanismos involucrados en la resistencia tumoral en leucemias, haciendo especial énfasis en el papel que desempeñan las células madre leucémicas y el metabolismo tumoral en la quimiorresistencia de este grupo de enfermedades. El conocimiento de los mecanismos de resistencia tumoral, así como el entendimiento detallado de las interacciones entre las células normales y leucémicas en el microambiente de la médula ósea, son prometedores blancos terapéuticos de las leucemias agudas.

Abstract Acute leukemias (AL) are clonal disorders originated from multi-potent immature hematopoietic cells and are characterized by aberrant proliferation, differentiation and maturation of leukemic progenitor cells as a result of multiple genetic and epigenetic events. Even though different chemotherapy regimens have been implemented to improve patient prognostic, acute leukemias represent a hematological malignancy with poor clinical outcome and low survival rates in pediatric and adult patients in Colombia. One of the main obstacles to the success of cancer treatment is the development of drug resistance during chemotherapy and the recurrent disease. In the study of tumor cells biology, it is now known that clonal evolution and oncogenic changes of tumor cells are biological properties that confer resistance mechanisms to conventional chemotherapy, which in turn translate into an increased mortality rate and/or an increased risk of relapse in leukemia patients. Therefore, the study of mechanisms that leukemic cells employ to avoid the cytotoxic effects of some chemotherapeutics is a main objective of cancer research. In this context, the objective of the current paper is to give a detailed information about recent advances in mechanisms involved in leukemic resistance, with special emphasis on the role of leukemic stem cells theory and tumor metabolism.

Subtype specific biomarkers associated with chemoresistance in epithelial ovarian cancer

In spite of the advent of many high throughput technologies, tumor tissue biomarkers are still the gold standard for diagnosis and prognosis of different malignancies including epithelial ovarian cancer (EOC). EOC is a heterogeneous disease comprised of five major subtypes which show distinct clinicopathological features and therapy response. Acquirement of chemoresistance toward therapy is a major challenge for successful treatment outcome in EOC patients. Several markers have been tested by immunohistochemical method to evaluate their prognostic merit to predict clinical outcome. However, a vast majority of such markers have been assessed for high-grade serous and clear cell ovarian cancer, among all subtypes of EOC. The current review elaborates upon those biomarkers that can potentially predict chemoresistance with subtype specificity.