Reverse effect of curcumin on CDDP-induced drug-resistance via Keap1/p62-Nrf2 signaling in A549/CDDP cell

OBJECTIVE@#To assess the effect of curcumin on CDDP-induced drug resistance and explore the underlying molecular mechanism through Nrf2 system and autophagy pathway.@*METHODS@#A drug-resistant cell model was established by exposing A549/CDDP cell to 2 μg/mL CDDP. A549/CDDP cell was treated with 20 μg/mL CDDP and 10 μM curcumin. The cell viability and apoptosis level, the signals of Keap1/P62-Nrf2 and autophagy pathway were analyzed.@*RESULTS@#CDDP induction promoted drug-resistant phenotype in A549/CDDP cell and activated autophagy as well as Nrf2 signals in A549/CDDP cell. Meanwhile, curcumin combination attenuated autophagy and Nrf2 activation induced by CDDP, and reversed the drug-resistant phenotype. Notably, curcumin combination augmented Keap1 transcription. Furthermore, Keap1 ablation with short hairpin RNAs hampered the efficacy of curcumin, suggesting Keap1 played a crucial role on reversal effect of curcumin.@*CONCLUSIONS@#The present findings demonstrate that CDDP promotes abnormal activation of Nrf2 pathway and autophagy, leading to drug resistance of A549/CDDP cell. Curcumin attenuates this process and combat drug-resistance through its potent activation on Keap1 transcription, which is essential for interplay between oxidative stress induced Nrf2 activation and autophagy/apoptosis switch.

Reverse effect of curcumin on CDDP-induced drug-resistance via Keap1/p62-Nrf2 signaling in A549/CDDP cell

Objective To assess the effect of curcumin on CDDP-induced drug resistance and explore the underlying molecular mechanism through Nrf2 system and autophagy pathway. Methods A drug-resistant cell model was established by exposing A549/CDDP cell to 2 μg/mL CDDP. A549/CDDP cell was treated with 20 μg/mL CDDP and 10 μM curcumin. The cell viability and apoptosis level, the signals of Keap1/P62-Nrf2 and autophagy pathway were analyzed. Results CDDP induction promoted drug-resistant phenotype in A549/CDDP cell and activated autophagy as well as Nrf2 signals in A549/CDDP cell. Meanwhile, curcumin combination attenuated autophagy and Nrf2 activation induced by CDDP, and reversed the drug-resistant phenotype. Notably, curcumin combination augmented Keap1 transcription. Furthermore, Keap1 ablation with short hairpin RNAs hampered the efficacy of curcumin, suggesting Keap1 played a crucial role on reversal effect of curcumin. Conclusions The present findings demonstrate that CDDP promotes abnormal activation of Nrf2 pathway and autophagy, leading to drug resistance of A549/CDDP cell. Curcumin attenuates this process and combat drug-resistance through its potent activation on Keap1 transcription, which is essential for interplay between oxidative stress induced Nrf2 activation and autophagy/apoptosis switch.

A prospective randomized controlled clinical trial of irinotecan plus cisplatin versus gemcitabine plus cisplatin as a first-line treatment for advanced non-small cell lung cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To prospectively evaluate the efficacy and toxicity of irinotecan plus cisplatin (IP regimen) compared with gemcitabine plus cisplatin (GP regimen) as a first-line treatment for advanced non-small cell lung cancer (NSCLC).</p><p><b>METHODS</b>A total of 63 patients were randomly assigned to two regimens. IP Group (31 patients): irinotecan 100 mg/m(2), iv, d1 and d8; cisplatin 25 mg/m(2), iv, d1 to d3, and 3 weeks a cycle. GP Group (32 patients): gemcitabine 1000 mg/m(2), d1 and d8; cisplatin 25 mg/m(2), iv, d1 to d3, and 3 weeks a cycle. All the patients at least received two cycles of therapy. The response rate (RR), disease control rate (DCR), median time to tumor progression (TTP), median survival time (MST), l-year survival rate, and side effects were observed.</p><p><b>RESULTS</b>Among the 31 cases of IP group, 8 patients had PR, 17 patients had SD and 6 patients had PD. The RR and DCR were 25.8% (8/31) and 80.6% (25/31), respectively. The TTP was 6.7 months, MST was 11.2 months and the 1-year survival rate was 45.2% (14/31). Among 32 cases in the GP group, 11 patients had PR, 18 patients had SD and 3 patients had PD. The RR and DCR were 34.4% (11/32) and 90.6% (29/32), respectively. The TTP was 6.5 months, MST was 11.0 months and the 1-year survival rate was 43.7% (14/32). The main side effects of the two groups included hematologic toxicities, digestive tract reaction and hair loss. The incidence of diarrhea in the IP group was significantly higher than that in the GP group (P < 0.05), but the incidence of thrombocytopenia in the GP group was significantly higher than that in the IP group (P < 0.01).</p><p><b>CONCLUSIONS</b>Our findings demonstrate that the two regimens have similar efficacy as a first-line treatment for advanced NSCLC. The major toxicities of the two regimens are well tolerable.</p>

Comparison between the effects of irinotecan or oxaliplatin combined with capecitabine in the treatment of advanced gastric cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To observe and compare the response rate and toxicity of irinotecan or oxaliplatin combined with capecitabine in the treatment of advanced gastric cancer.</p><p><b>METHODS</b>Sixty-three patients with advanced gastric cancer were randomly divided into two groups. The CPT-11 + CAP group consisted of 32 patients who received irinotecan plus capecitabine: CPT-11 100 mg/m(2) was injected in 90 minutes on d 1, 8;capecitabine 2000 mg/m(2), bid, with the first dose in the evening of day 1 and last dose the morning of day 15, repeated for every 21 days. The L-OHP + CAP group consisted of 31 patients who received oxaliplatin plus capecitabine: oxaliplatin 100 mg/m(2) on day 1, capecitabine 2000 mg/m(2), bid, with the first dose in the evening of day 1 and last dose the morning of day 15, repeated for every 21 days. Two or more cycle chemotherapy was completed in each group.</p><p><b>RESULTS</b>In the CPT-11 + CAP group, no patient achieved complete response and 13 patients achieved partia1 response. The overall response rate was 40.6% (13/32), and the median progression-free survival time was 6.3 months. In the L-OHP + CAP group, no patient achieved complete response and 12 patients achieved partial response. The overall response rate was 38.7% (12/31), and the median progression-free survival time was 6.1 months. There was no significant difference between them (P > 0.05). The most common toxicities were gastrointestinal reaction, peripheral neuropathy and myelosuppression in the two groups. Patients in CPT-11 + CAP group experienced more III/IV diarrhea (28.1%/3.2%, P = 0.018). On the contrary, the rate of III/IV neurotoxicity in the group B was higher (25.8%/3.1%, P = 0.027). No chemotherapy-related death occurred.</p><p><b>CONCLUSION</b>The therapeutic effects of irinotecan or oxaliplatin combined with capecitabine in the treatment of advanced gastric cancer are good and comparable, and their toxicities are tolerable.</p>