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Transmembrane proteins(TMEMs)are a class of family proteins that span lipid bilayers,serving as crucial channel proteins on biological membranes,playing essential physiological roles.TMEMs′ over-expression in malignant tumors,such as TMEM16A and TMEM206,has been linked to the promotion of malignancy.Conversely,down-regulation of TMEM100 expression has been associated with tumor progression.TMEM98,whose expression varies across different malignancies.TMEMs has shown promise as both a therapeutic target and a prognostic marker in cancer.Additionally,TMEMs play a vital role in various malignancies by modulating the Wnt and AKT signaling pathways through interaction with different upstream and downstream regulatory factors.Furthermore,research has provided additional insights into their role in cisplatin-related chemoresistance in specific malignant tumor cell populations.
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@#This is the first reported case of the use of immunotherapy in chemo-resistant Gestational Trophoblastic Neoplasia (GTN) in the country. A 41-year-old, Gravida 4 Para 3 (3013) with a diagnosis of GTN, Stage III: WHO risk score of 13 (Choriocarcinoma) was initially managed with 10 cycles of multiple agent Etoposide, Methotrexate, Actinomycin D- Cyclophosphomide and Vincristine (EMACO) and 19 cycles of Etoposide, Cisplatin- Etoposide Methotrexate and Actinomycin D (EP-EMA). With continuous rise in beta human chorionic gonadotropin (ßhCG) levels, the patient was referred to a Trophoblastic Disease Center where there was note of tumor progression to the brain. She was started on third-line salvage chemotherapy of Paclitaxel and Carboplatin (PC) with concomitant whole brain irradiation completing three cycles after which chemoresistance was again diagnosed with increasing hCG titers and increase in the number and size of the pulmonary masses which were deemed unresectable. Immunotherapy was started with Pembrolizumab showing a good response with marked fall in ßhCG levels. The onset of immune-related adverse events (irAEs) caused a marked delay in subsequent cycles of immunotherapy. With management of the irAEs, two more cycles of Pembrolizumab with fifty percent dose reduction were given with corresponding drop in ßhCG levels. However, the patient subsequently developed gram-negative septicemia with possible hematologic malignancy and finally succumbed to massive pulmonary embolism. The case highlights the importance of prompt diagnosis and referral to a Trophoblastic Disease Center and the use of immunotherapy in chemo-resistant GTN.
Subject(s)
Gestational Trophoblastic Disease , ChoriocarcinomaABSTRACT
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.
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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.
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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.
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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.
Subject(s)
Humans , Esophageal Squamous Cell Carcinoma/drug therapy , Cisplatin/metabolism , Esophageal Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Carcinoma, Squamous Cell/genetics , Growth Differentiation Factor 15/therapeutic use , Receptor, Transforming Growth Factor-beta Type II/therapeutic use , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, NeoplasticABSTRACT
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.
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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.
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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.
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Objective:colorectal cancer is one of the common malignant tumors in the gas-trointestinal tract.Oxaliplatin is the first-line drug for the treatment of advanced colorectal cancer,but drug resistance often occurs.The mechanism of CXCR4 in oxaliplatin resistance of colon cancer is not clear.This study intends to explore the mechanism of CXCR4 mediated oxaliplatin resistance and the potential therapeutic value of CXCR4 inhibitor AMD3100.Methods:oxaliplatin resistant strains HCT116 were constructed.The expression of CXCR4 and the phosphorylation level of PI3K-Akt signal pathway were detected by Q-PCR and Western blot.The phosphorylation level of PI3K-Akt signal pathway was detected by Q-PCR and Western blot.The effect of AMD3100 an-tagonizing CXCR4 or combined application of Akt inhibitor LY294002 on oxaliplatin resistance of drug-resistant cells was detected by CCK8.Results:CCK-8 was used to detect the proliferation activity of Oxaliplatin in HCT116 drug resistant group compared with control cells in the absence of drugs and at different concentrations.The results showed that there was no significant change in the activity of the resistant strains,while the control cells showed a significant decrease.Q-PCR and Western blot showed that the expression of CXCR4 and the phosphorylation level of PI3K-Akt increased significantly in the drug-resistant group(P<0.05).After administration of CXCR4 inhibitor AMD3100,CXCR4 expression and PI3K-Akt phosphorylation decreased significantly(P<0.05).AMD3100 enhanced the sensitivity of drug-resistant cell lines to oxaliplatin.The combination of AMD3100 and Akt inhibitor LY294002 can further enhance the sensitivity of drug-resistant cell lines to oxaliplatin.Conclusion:CXCR4 mediated activation of PI3K-Akt signaling pathway plays an important role in the resistance of colon cancer to oxaliplatin.AMD3100 may become a potential therapeutic drug against chemoresistance of colon cancer.
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Aim To explore the possibility of resveratrol ( RES) combined with irinotecan ( IRI) in the treatment of colorectal cancer ( CRC ) and the underlying molecular mechanism of RES ameliorating IRI chemoresistance of CRC cells. Methods CRC cells used in this study were HT-29 and RKO cells. The effects of RES, IRI and their combination on the proliferation of CRC cells were analyzed by MTT assay and colony formation assay. The effects of RES,IRI and their combination on the migration of CRC cells were assessed by Wound-healing assay. On this basis,the role of RES in regulating IRI chemoresistance of CRC cells and the underlying molecular mechanisms were further explored. Results The proliferation and migration ability of CRC cells in the RES and IRI combined treatment group were significantly lower than those in the IRI treated group, which showed that RES could enhance the inhibiting effect of IRI on the proliferation and migration of CRC cells, indicating that RES was able to a-meliorate the chemoresistance of CRC cells to IRI. And remarkably lower marker proteins expression levels of EGFR/AKT/mTOR signaling pathway in the RES and IRI combined treatment group was observed. Moreover, both EGFR activator (NSC 228155) and AKT activator (SC79) could reverse the ameliorating effect of RES on IRI chemoresistance of CRC cells, whereas AKT inhibitor (MK2206 ) could partially reverse the effect of NSC 228155. Conclusions RES can inhibit the proliferation and migration of CRC cells by down-regulating EGFR/AKT/mTOR signaling pathway, so as to ameliorate the chemoresistance of CRC cells to IRI, suggesting that RES combined with IRI can be a promising novel treatment for CRC.
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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.
Subject(s)
Humans , Proto-Oncogene Proteins c-akt/metabolism , Drug Resistance, Neoplasm , Cell Line, Tumor , TOR Serine-Threonine Kinases/metabolism , Fluorouracil/pharmacology , Cell Proliferation , Autophagy , Colorectal Neoplasms/drug therapyABSTRACT
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.
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@#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.
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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.
Subject(s)
Child , Humans , Apoptosis , Cell Line, Tumor , Cell Proliferation , Cytarabine , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Wnt Signaling Pathway , beta Catenin/geneticsABSTRACT
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
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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
Subject(s)
Gestational Trophoblastic DiseaseABSTRACT
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.
Subject(s)
Female , Humans , Pregnancy , Gestational Trophoblastic Disease/drug therapy , Multivariate Analysis , Retrospective Studies , Risk FactorsABSTRACT
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.
Subject(s)
Female , Humans , Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis , Carcinoma, Ovarian Epithelial/metabolism , Cell Line, Tumor , Cofilin 1/metabolism , Drug Resistance, Neoplasm , Ovarian Neoplasms/metabolism , Paclitaxel/therapeutic use , Phosphoprotein Phosphatases/metabolism , PhosphorylationABSTRACT
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.