Cisplatin (DDP) is the most widely used chemotherapy agent for treatment of malignancies including lung cancer. However, the effectiveness of DDP is often weakened by acquired resistance of tumor cells. DDP kills cancer cells primarily by creating intrastrand and interstrand DNA cross-links, which block DNA replication. The Fanconi anemia (FA)/BRCA pathway is a DNA cross-link damage repair pathway, which regulates cellular resistance to DNA cross-link agents, such as DDP. Some study has shown that natural compound curcumin sensitize human ovarian and breast cancer cells to DDP. However, whether curcumin may reverse resistance to DDP in DDP-resistant lung cancer cells has not been understood. In this study, we showed that curcumin enhanced the proliferation inhibitory effect of DDP and promote DDP-induced apoptosis in A549/DDP cells (DDP-resistant lung adenocarcinoma cells). Moreover, we observed that FA/BRCA pathway DNA damage repair processes, such as DDP-induced FANCD2 monoubiquitination and nuclear foci formation were downregulated in the presence of curcumin, suggesting that curcumin enhanced sensitivity to DDP in A549/DDP cells through the inhibition of FA/BRCA pathway. Furthermore, the calculation of q value and apoptosis analyses revealed that curcumin in combination with DDP could exert a synergistic cytotoxic effect in A549/DDP cells, further demonstrating that curcumin can reverse cisplatin resistance of A549/DDP cells. In conclusion, by suppressing the FA/BRCA pathway DNA repair, curcumin potentiates DDP-induced proliferation inhibitory effect and apoptosis in A549/DDP cell, indicating that curcumin may serve as a chemosensitizer to cross-link-inducing anticancer drugs DDP.
The NLRP3 inflammasome is an intracellular multiple-protein complex that controls the maturation and release of interleukin (IL)-1β and IL-18. Endogenous carbon monoxide (CO) is anti-inflammatory. The aim of this study was to assess the effects/mechanisms of CO-releasing molecule-3 (CORM-3)-dependent modulation of the NLRP3 inflammasome in cardiac fibroblasts (CF) and its effect on myocardial function in sepsis. CF were treated with CORM-3 or inactive CORM-3 (iCORM-3) before NLRP3 inflammasome priming with lipopolysaccharides (LPS) or following activation with adenosine triphosphate (ATP). In parallel, cardiomyocytes (CM) were challenged with supernatants of LPS/ATP-stimulated CF or a cytokine mixture (Cyto-mix) containing IL-1β, IL-18, and HMGB1. In vivo, mice were treated with CORM-3 before or after LPS to induce sepsis (endotoxemia). Pretreatment of CF with CORM-3 prevented an LPS-induced increase in NLRP3 and pro-IL-1β expression. Treatment of CF with CORM-3 before ATP prevented ATP-induced activation of the NLRP3 inflammasome. Challenging CF with LPS/ATP promoted NLRP3 interactions with adaptor ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), which was prevented by CORM-3. Challenging CM with supernatants of CF with LPS/ATP or Cyto-mix (IL-1β, IL-18, and HMGB1) resulted in CM apoptosis, which was attenuated with either a CORM-3 or IL-1 receptor antagonist. Finally, myocardial NLRP3 inflammasome activation and myocardial dysfunction in septic mice were abolished by CORM-3. In NLRP3-deficient mice with sepsis, CORM-3 did not show additional benefits in improving myocardial function. Our results indicate that CORM-3 suppresses NLRP3 inflammasome activation by blocking NLRP3 interactions with the adaptor protein ASC and attenuates myocardial dysfunction in mice with sepsis.
Our results indicate that the functional status of DNA repair pathways determine the sensitivity of NSCLC cells to cisplatin. Direct targeting of the pathway that is involved in cisplatin resistance may be an effective strategy to surmount cisplatin resistance in NSCLC.
BackgroundPrimary pleuropulmonary and mediastinal synovial sarcomas (PPMSSs) are extremely rare. The authors present the largest series in an Asian population.MethodsBetween 2000 and 2015, 26 genetically confirmed PPMSSs were included. The clinicopathologic features of all of the cases were reviewed. Immunohistochemical staining was carried out using the following antibodies: TLE1, cytokeratin (AE1/AE3), EMA, CD99, Bcl-2, CK7, CD34, S-100 protein, and Ki-67. The chromosomal translocation t(X;18)(p11.2;q11.2) was detected by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR). We compared the clinical, pathologic, immunohistochemical, and molecular features of this series with that of the previous series and soft tissue synovial sarcomas.ResultsThis series included 17 males and nine females. The median age was 36.5 years (range, 16–72 years). The tumors involved the lung (76.9 %), pleura (15.4 %), and mediastinum (7.7 %). The median tumor size was 6 cm (range 2.3 ~ 24 cm). The majority of the tumors were well-circumscribed. The tumors were classified as monophasic (84.6 %), biphasic (3.8 %), and poorly differentiated (11.5 %) types. The tumors were graded as French Federation of Cancer Centers (FNCLCC) grade 2 (62.5 %) and FNCLCC 3 (37.5 %). Diffuse immunostaining for TLE1, BCL-2, and CD99 was identified in 91.7, 95.7, and 56.0 % of the tumors, respectively. Focal positivity was seen with EMA (84.6 %), CK7 (55.6 %), cytokeratin (AE1/AE3) (68.0 %), CD34 (5.0 %), and S-100 protein (21.7 %). A high Ki-67 index (≥10 %) was observed in 91.3 % of the tumors. The fusion transcripts included SS18-SSX1 (15/22, 68.2 %), SS18-SSX2 including variants (6/22, 27.3 %), and SS18-SSX4 (1/22, 4.5 %) fusions. The remaining four cases showed positivity for SS18 rearrangement by FISH. Surgical excision of tumors or lobectomy were performed in 20 patients, and seven of the patients underwent adjuvant therapy. Clinical follow-up was available in 73.1 % cases, with a median follow-up of 12.0 months. The median survival time was 14.5 months. Tumor resection (p = 0.024) and no residual tumor (p = 0.004) were associated with an improved overall survival time.ConclusionsPPMSS is a highly aggressive neoplasm. Extensive surgical resection of the tumor and more effective adjuvant therapy should be advocated. PPMSS must be differentiated from similar diseases.
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