Anaplastic lymphoma kinase (ALK) fusions represent the second most common oncogenic driver mutation in non-small cell lung cancer (NSCLC). As the new class of 3rd generation of ALK tyrosine kinase inhibitor (TKI), lorlatinib has shown robust potency and brain-penetrant clinical activity against a wide spectrum of multiple resistance mutations within the ALK domain detected during crizotinib and 2nd generation ALK TKI treatment. Lorlatinib is generally well-tolerated with unique adverse drug reaction/adverse event, including hyperlipidemia and central nervous system effects, which are mostly mild to moderate severity and manageable through dosage modifications and/or standard medical intervention. For advanced NSCLC with ALK positivity, patients should be evaluated for baseline characteristics and pre-existing medication, informed of the potential toxicities, and periodically monitored to balance benefits and risks. Moreover, a multidisciplinary group of experts is essential to establish a comprehensive diagnostic and therapeutic strategy.
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Aminopyridines ; Carcinoma, Non-Small-Cell Lung/pathology* ; China ; Consensus ; Drug Resistance, Neoplasm/genetics* ; Drug-Related Side Effects and Adverse Reactions/drug therapy* ; Humans ; Lactams ; Lactams, Macrocyclic/adverse effects* ; Lung Neoplasms/pathology* ; Protein Kinase Inhibitors/adverse effects* ; Protein-Tyrosine Kinases/genetics* ; Pyrazoles

OBJECTIVE: To investigate the effect of interleukin-17A (IL-17A) on chemosensitivity of ovarian cancer cells to cisplatin (DDP) and explore the mechanism in light of autophagy regulation. METHODS: Ovarian cancer SKOV3 cells cultured RESULTS: DDP increased the expression of IL-17RA in ovarian cancer SKOV3 cells. Treatment with IL-17A significantly reduced the susceptibility of SKOV3 cells to cisplatin-induced apoptosis ( CONCLUSIONS IL-17A/IL-17RA can decrease chemosensitivity of SKOV3 cells to DDP by upregulating DDP-induced autophagy.
Antineoplastic Agents/therapeutic use* ; Apoptosis/drug effects* ; Autophagy/drug effects* ; Cell Line, Tumor ; Cell Proliferation/drug effects* ; Cisplatin/pharmacology* ; Drug Resistance, Neoplasm/drug effects* ; Female ; Humans ; Interleukin-17/pharmacology* ; Ovarian Neoplasms/drug therapy* ; Receptors, Interleukin-17

Chronic myeloid leukemia (CML) is one of the most common hematological malignancies and characterized by the formation of Philadelphia (Ph) chromosome. Recently, tyrosine kinase inhibitors (TKI) treatment greatly improved the prognosis of CML. However, the options may be limited when a patient develops traditional TKI resistance or gene mutation. Herein, we reported a case. A 38-year-old male CML patient developed a BCR-ABL1 gene mutation of T315I after 2.5 years of TKI treatment, including imatinib and dasatinib. We adjusted the treatment with the combined application of dasatinib and axitinib. BCR-ABL1 gene copies dropped down and achieved an early molecular response at 2 months later. Subsequently, he received hematopoietic stem cell transplantation. Axitinib and dasatinib were applied for another half year after the allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two years after the allo-HSCT, the BCR-ABL1 gene was still undetectable. It provided a successful example in treating CML patients carrying BCR-ABL1 T315I mutation via combination of axitinib with conditional TKI.
Adult ; Axitinib ; Dasatinib ; therapeutic use ; Drug Resistance, Neoplasm ; drug effects ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; genetics ; Male ; Mutation ; Protein Kinase Inhibitors ; therapeutic use

Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality globally. It accounts for the majority of primary liver cancer cases. Amyloid precursor protein (APP), a cell membrane protein, plays a vital role in the pathogenesis of Alzheimer's disease, and has been found to be implicated in tumor growth and metastasis. Therefore, to understand the relationship between APP and 5-fluorouracil (5-FU) resistance in liver cancer, Cell Counting Kit-8, apoptosis and cell cycle assays, western blotting, and reverse transcription-quantitative polymerase chain reaction (qPCR) analysis were performed. The results demonstrated that APP expression in Bel7402-5-FU cells was significantly up-regulated, as compared with that in Bel7402 cells. Through successful construction of APP-silenced (siAPP) and overexpressed (OE) Bel7402 cell lines, data revealed that the Bel7402-APP^751-OE cell line was insensitive, while the Bel7402-siAPP cell line was sensitive to 5-FU in comparison to the matched control group. Furthermore, APP overexpression decreased, while APP silencing increased 5-FU-induced apoptosis in Bel7402 cells. Mechanistically, APP overexpression and silencing can regulate the mitochondrial apoptotic pathway and the expression of apoptotic suppressor genes (B-cell lymphoma-2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl)). Taken together, these results preliminarily revealed that APP overexpression contributes to the resistance of liver cancer cells to 5-FU, providing a new perspective for drug resistance.
Amyloid beta-Protein Precursor/physiology* ; Apoptosis/drug effects* ; Carcinoma, Hepatocellular/drug therapy* ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Fluorouracil/pharmacology* ; Humans ; Liver Neoplasms/drug therapy* ; Mitochondria/physiology* ; Proto-Oncogene Proteins c-bcl-2/genetics* ; bcl-X Protein/genetics*

BACKGROUND: Lung cancer is one of the common malignant tumors that impair human health. With the development of epigenetics, the researchers found that enhancer of Zeste homolog 2 (EZH2) is highly expressed in lung cancer tissue and its expression is closely related to the prognosis. EZH2 inhibitor can also enhance the sensitivity of tumor cells to a variety of anti-tumor drugs. The purpose of this study is to investigate the effect of combination of EZH2 inhibitor and gefitinib on the proliferation, apoptosis and migration of Gefitinib-resistant lung cancer cells. METHODS: PC9 and PC9/AB2 cells were used for this study. CCK-8 and EdU experiment were used to detect combined treatment on cell viability and proliferation activity; Wound healing assay and Transwell chamber experiment were used to determine the effects of combination therapy on cell migration ability; Flow cytometry was used to detect the effect of combination therapy on EZH2 and apoptosis; Western blot was used to observe the effect of combination therapy on epidermal growth factor receptor (EGFR) signaling pathway-related proteins expression. RESULTS: In gefitinib-resistant cell line PC9/AB2, gefitinib combined with EZH2 inhibitor GSK343 can significantly inhibit cell viability, reduce cell migration and increase cell apoptosis. At the same time, combination therapy can significantly inhibit the expression of EZH2 and phosphorylation EGFR proteins. CONCLUSIONS The combination of EZH2 inhibitor GSK343 and gefitinib sensitize PC9/AB2 cell to gefitinib response. This study also suggests that synergistic therapy plays a role in the reversal of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) resistance in lung cancer.
Antineoplastic Agents ; pharmacology ; Cell Line, Tumor ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Cell Survival ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Drug Synergism ; Enhancer of Zeste Homolog 2 Protein ; antagonists & inhibitors ; ErbB Receptors ; antagonists & inhibitors ; Gefitinib ; pharmacology ; Humans ; Lung Neoplasms ; pathology ; Protein Kinase Inhibitors ; pharmacology

OBJECTIVE: To investigate the effect of Quercetin (Qu) on cell proliferation, apoptosis and cell cycle, as well as the expression changes of Wnt/β-catenin signaling pathway, apoptosis and cell cycle regulators and BCR-ABL in CML susceptible cells K562 and imatinib-resistant cells (IM) K562R. METHODS: The trypan blue staining was used to detect the all proliferation. The cell cycle and apoptosis were detected by flow cytometry. The fluorescence quantitative PCR and Western blot were used to detect the expression of mRNA and protein respectively. RESULTS: After administration with 5, 10, 20, 40, 80, 160, 320 μmol/L Qu, the inhibition ratio in K562 cells was 5.07%, 5.98%, 11.09%, 31.88%, 56.89%, 70.44%, 86.63%; and that in K562R cells were 4.99%, 9.75%, 10.54%, 8.93%, 25.13%, 46.89%, 68.60%; IC of K562 and K562R was 76.4 μmol/L and 230.2 μmol/L, respectively. Flow cytometry showed that Qu (50, 100 and 200 μmol/L) could induce cell apoptosis and cell cycle arrest in a dose-dependent manner (r=0.9914, r=0.9871 respectively). After treatment with Qu (100 μmol/L)，the expressions of mRNA (P＜0.05) and protein(except Caspase-9) expression of Caspase-3, 8 and 9, p21 and p27 increased in K562 cells as compared with control, but the protein expression of p27 and Caspase-3 not changed in K562R. Qu (100 μmol/L) could decrease the mRNA(P＜0.05) and protein levels of Wnt/β-catenin signaling pathway members GSK-3β, β-catenin, Lef-1 and the downstream targets PPAR-δ and Cyclin D1 compared with control. The PCR results showed that Qu could reduce the BCR-ABL mRNA expression in CML cells, but the protein expression of BCR-ABL and p-BCR-ABL not obviouly changed. CONCLUSION Qu can inhibit the proliferation K562 and K562R cells, and decrease the drug resistance and increase the sensitivity, that relate with inhibiting Wnt/β-catenin signaling pathway, activating apoptosis pathway and cyclins.
Apoptosis ; Cell Proliferation ; Drug Resistance, Neoplasm ; Glycogen Synthase Kinase 3 beta ; Humans ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; Quercetin ; Wnt Signaling Pathway ; drug effects ; beta Catenin

OBJECTIVE: To investigate the effects of ethanol extract of Patrinia scabiosaefolia (EEPS) on chemo-resistance of colorectal cancer cells (CRC) and explore the possible molecular mechanisms. METHODS: 5-fluorouracil (5-FU)-resistant human colorectal carcinoma cell line (HCT-8/5-FU) and its parental cells HCT-8 were treated with EEPS (0, 0.25, 0.50, 1 or 2 mg/mL), or 5-FU (0, 100, 200, 400, 800 or 1600 μmol/L). The 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was performed to evaluate the cell viability. Cell density was observed by phase-contrast microscope, cell counting and colony formation assay were used to determine the cell proliferation of HCT-8/5-FU cells treated with 0, 0.5, 1 or 2 mg/mL EEPS. Cell apoptosis was determined by Hoechst staining. Western-blot was performed to detect the phosphorylation of AKT as well as the protein expression level of B-cell CLL/lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax). RESULTS: Compared with HCT-8 cells, MTT assay results indicated that HCT-8/5-FU cells were resistant to 5-FU treatment (P<0.05), and sensitive to EEPS treatment (P>0.05). Moreover, compared with untreated HCT-8/5-FU cells, 1 and 2 mg/mL of EEPS treatment significantly reduced cell density, cell number, inhibited cell survival (P<0.05), and induced apoptosis in HCT-8/5-FU cells. Furthermore, 1 and 2 mg/mL of EEPS significantly decreased the phosphorylation level of p-AKT and Bcl-2 protein expression, and increased the expression of Bax protein (P<0.05). CONCLUSION EEPS is a promising therapeutic agent that may overcome chemo-resistance in cancer cells, likely through suppression of the AKT pathway and promotion of cancer cell apoptosis.
Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cell Survival ; drug effects ; Colorectal Neoplasms ; drug therapy ; pathology ; Drug Resistance, Neoplasm ; drug effects ; Fluorouracil ; pharmacology ; therapeutic use ; Humans ; Patrinia ; chemistry ; Phosphorylation ; drug effects ; Proto-Oncogene Proteins c-akt ; metabolism ; Signal Transduction ; drug effects ; Tumor Stem Cell Assay ; bcl-2-Associated X Protein ; metabolism

Eight new annonaceous acetogenins, squamotin A-D (1-4), annosquatin IV-V (5 and 6), muricin O (7) and squamosten B (8), together with four known ones (9-12) were isolated from the seeds of Annona squamosa. Their structures were elucidated by chemical methods and spectral data. The inhibitory activities of compound 1-9 against three multidrug resistance cell lines were evaluated. All tested compounds showed strong cytotoxicity.
Acetogenins ; chemistry ; isolation & purification ; pharmacology ; toxicity ; Annona ; chemistry ; Antineoplastic Agents, Phytogenic ; chemistry ; isolation & purification ; pharmacology ; toxicity ; Cell Line, Tumor ; Cell Survival ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Drug Screening Assays, Antitumor ; Humans ; Molecular Structure ; Plant Extracts ; chemistry ; pharmacology ; toxicity ; Seeds ; chemistry

Resistance to cisplatin (DDP)-based chemotherapy is a major cause of treatment failure in human gastric cancer (GC). It is necessary to identify the drugs to re-sensitize GC cells to DDP. In our previous research, Zuo Jin Wan Formula (ZJW) has been proved could increase the mitochondrial apoptosis via cofilin-1 in a immortalized cell line, SGC-7901/DDP. Due to the immortalized cells may still difficult highly recapitulate the important molecular events in vivo, primary GC cells model derived from clinical patient was constructed in the present study to further evaluate the effect of ZJW and the underlying molecular mechanism. Immunofluorescent staining was used to indentify primary cultured human GC cells. Western blotting was carried out to detect the protein expression. Cell Counting Kit-8 (CCK-8) was used to evaluate cell proliferation. Flow cytometry analysis was performed to assess cell apoptosis. ZJW inhibited proliferation and induced apoptosis in primary DDP-resistant GC cells. Notably, the apoptosis in GC cells was mediated by inducing cofilin-1 mitochondrial translocation, down-regulating Bcl-2 and up-regulating Bax expression. Surprisingly, the level of p-AKT protein was higher in DDP-resistant GC cells than that of the DDP-sensitive GC cells, and the activation of AKT could attenuate ZJW-induced sensitivity to DDP. These data revealed that ZJW can increase the chemosensitivity in DDP-resistant primary GC cells by inducing mitochondrial apoptosis and AKT inactivation. The combining chemotherapy with ZJW may be an effective therapeutic strategy for GC chemoresistance patients.
Adult ; Aged ; Aged, 80 and over ; Apoptosis ; drug effects ; Cell Proliferation ; drug effects ; Cisplatin ; pharmacology ; therapeutic use ; Cofilin 1 ; metabolism ; Drug Resistance, Neoplasm ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Female ; Humans ; Male ; Middle Aged ; Mitochondria ; drug effects ; metabolism ; pathology ; Proto-Oncogene Proteins c-akt ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Stomach Neoplasms ; drug therapy ; metabolism ; pathology ; Tumor Cells, Cultured

OBJECTIVE: To study the effects of the overexpression of autophagy-related gene 3 (ATG3) on autophagy and salinomycin-induced apoptosis in breast cancer cells and explore the underlying mechanisms. METHODS: We used the lentivirus approach to establish a breast cancer cell line with stable overexpression of ATG3. Western blotting, immunofluorescence staining and transmission electron microscopy were used to analyze the effect of ATG3 overexpression on autophagy in breast cancer MCF-7 cells. Using the AKT/mTOR agonists SC79 and MHY1485, we analyzed the effect of AKT/mTOR signal pathway activation on ATG3 overexpression-induced autophagy. Western blotting and flow cytometry were used to analyze the effect of autophagy on apoptosis of the ATG3-overexpressing cells treated with salinomycin and 3-MA (an autophagy inhibitor). RESULTS: In ATG3-overexpressing MCF-7 cells, ATG3 overexpression obviously promoted autophagy, inhibited the AKT/mTOR signaling pathway, significantly weakened salinomycin-induced apoptosis ( < 0.01), caused significant reduction of the levels of the pro-apoptotic proteins cleaved-caspase 3 ( < 0.01) and Bax ( < 0.05), and enhanced the expression of the anti-apoptotic protein Bcl-2 ( < 0.05). The inhibition of autophagy obviously weakened the inhibitory effect of ATG3 overexpression on salinomycin-induced apoptosis. CONCLUSIONS ATG3 overexpression promotes autophagy possibly by inhibiting the AKT/mTOR signaling pathway to decrease salinomycin-induced apoptosis in MCF-7 cells, suggesting that autophagy induction might be one of the mechanisms of drug resistance in breast cancer cells.
Acetates ; pharmacology ; Apoptosis ; drug effects ; genetics ; Autophagy ; drug effects ; Autophagy-Related Proteins ; metabolism ; Benzopyrans ; pharmacology ; Breast Neoplasms ; metabolism ; pathology ; Cell Line, Tumor ; Cell Proliferation ; Drug Resistance, Neoplasm ; Female ; Gene Expression Regulation ; Humans ; MCF-7 Cells ; Morpholines ; pharmacology ; Proto-Oncogene Proteins c-akt ; antagonists & inhibitors ; metabolism ; Pyrans ; pharmacology ; TOR Serine-Threonine Kinases ; antagonists & inhibitors ; metabolism ; Triazines ; pharmacology ; Ubiquitin-Conjugating Enzymes ; metabolism