Anticancer effects of ß-elemene with hyperthermia in lung cancer cells.

ß-elemene is a novel, plant-derived anticancer drug, which has been used to target multiple solid tumor types. Hyperthermia is an adjuvant therapeutic modality to treat cancer. However, the underlying mechanisms associated with the efficacy of these two treatments are largely unknown. The aim of the present study was to evaluate the effects of ß-elemene combined with hyperthermia in lung cancer cell lines. An MTT assay was used to determine cell viability. The cell cycle and apoptosis were analyzed using flow cytometry. The morphology of cells during apoptosis was determined using a transmission electron microscope. The expression levels of P21, survivin, caspase-9, B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax) mRNA were detected using quantitative polymerase chain reaction. ß-elemene with hyperthermia treatment significantly inhibited the viability and increased the apoptosis rate of A549 cells compared with ß-elemene treatment alone (P<0.01), and significantly decreased the proportion of cells in S phase compared with the control (P<0.01). Morphological observation using transmission electron microscopy indicated cross-sectional features of apoptosis: Chromatin condensation, reduced integrity of the plasma membrane, increased cellular granularity, nuclear collapse and the formation of apoptotic bodies. ß-elemene with hyperthermia treatment significantly promoted P21 and Bax mRNA expression (P<0.01) and significantly decreased caspase-9, Bcl-2 and survivin mRNA expression (P<0.01) in A549 cells. In conclusion, ß-elemene with hyperthermia has a significant inhibitory effect on A549 cells. This occurs through reducing S phase and inducing apoptosis, via an increase in P21 and Bax expression and a decrease in caspase-9, Bcl-2 and survivin expression.

The effects of SAHA on radiosensitivity in pancreatic cancer cells by inducing apoptosis and targeting RAD51.

Suberoyl anilide hydroxamic acid (SAHA) is one of the most promising Histone deacetylases(HDAC) inhibitors which has shown significant anti-tumor activity for many malignancies. We explored the potential mechanism of the radiosensitivity effect of SAHA in Panc-1 cells and attempted to develop SAHA as a systemic treatment strategy for pancreatic cancer. Growth inhibition was detected by CCK-8 assay. Radiosensitizing enhancement ratio was determined by clonogenic assay. The cell cycle and apoptosis assay was detected using flow cytometry and annexin-V/PI. The level of Bax, Bcl-2, Ku70, Ku86, RAD51, RAD54 protein expression were detected using Western blot analysis. Gene silencing was processed by lentiviral vector and qRT-PCR was performed to detect mRNA expression. The results revealed that SAHA inhibited the proliferation of Panc-1 cells. SAHA enhanced the radiosensitivity with a sensitization enhancement ratio(SER) of 1.10 of the Panc-1 cells. SAHA induced G2-M phase arrest and apoptosis of Panc-1 cells with radiation. SAHA upregulated Bax and downregulated Bcl-2, Ku70, Ku86, RAD51, RAD54 protein expression of irradiated Panc-1 cells. SAHA enhanced the radiosensitivity of Panc-1 cells by modulating RAD51 expression. SAHA enhanced radiosensitivity to pancreatic carcinoma Panc-1 cells. It was associated with the G2-M phase arrest and apoptosis via modulation of Bax and Bcl-2 expression. Downregulation of Ku70, Ku86, RAD51 and RAD54 expression caused suppression of HR-mediated DNA repair. SAHA is a good radiosensitizer for pancreatic cancer treatment.

Anti-PD-1/PD-L1 Therapy as a Promising Option for Non-Small Cell Lung Cancer: a Single arm Meta-Analysis.

Anti-PD-1/PD-L1 antibodies showed satisfactory efficacy in treating non-small-cell lung cancer. We conducted this meta-analysis to explore the advantage subtypes and best therapeutic modalities of Anti-PD-1/PD-L1 therapy on NSCLC. A quantitative meta-analysis was performed through a systematic search in PubMed, Web of Science, and the Cochrane Library. The pooled ORR, 6-month progression-free survival rate (PFSR6m), and 1-year overall survival rate (OSR1y) were calculated and compared. 15 trials were included in this meta-analysis. Our analyses demonstrated the pooled ORR of 1st line and 2nd or more line anti-PD-1/PD-L1 therapy were 36.5% (21.9-51.0%) and 17.0% (14.3-19.7%), respectively. While the difference was significant (Z = 3.31, p < 0.001). The pooled ORR for non-squamous and squamous cell lung cancer were 18.5% (16.0-21.1%) and 17.9% (14.4-21.5%), respectively. The difference was not significant (Z = 0.27, p = 0.791). The pooled ORR for PD-L1 positive and negative patients were 29.6% (21.6-37.6%) and 13.5% (10.6-16.3%), respectively. The difference was significant (Z = 4.39, p < 0.001). The PFSR6m for PD-L1 positive and negative NSCLC were 50.0% (40.5-62.3%) and 27.0% (19.2-34.7%). The difference was significant (Z = 3.72, p < 0.001). The OSR1y for PD-L1 positive and negative NSCLC were 66.8% (44.8%-88.9%) and 54.0% (32.6-75.3%). The difference was not significant (Z = 0.77, p = 0.441). Anti-PD-1/PD-L1 antibody can serve as a promising treatment option for NSCLC. Patients with positive PD-L1 expression may benefit more from anti-PD-1/PD-L1 therapy. 1st-line anti-PD-1/PD-L1 therapy can be chosen as the best modality. Squamous cell lung cancer also benefit from anti-PD-1/PD-L1 therapy.

Effect of Hyperthermic Intraperitoneal Perfusion Chemotherapy in Combination with Intravenous Chemotherapy as Postoperative Adjuvant Therapy for Advanced Gastric Cancer.

BACKGROUND/AIMS: The aim is to evaluate the preliminary efficacy and side effects of paclitaxel, 5-fluorouracil, and leucovorin intravenous chemotherapy in combination with cisplatin hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) as postoperative adjuvant therapy for patients of locally advanced gastric cancer (GC) at high risk for recurrence after curative resection. METHODOLOGY: Four GC patients who underwent radical gastrectomy with D2 lymphadenectomy were enrolled. All patients received paclitaxel 135 mg/m2 on day 1, 5-FU 500 mg/m2 on days 1-5, LV 200 mg/m2 on days 1-5 intravenous chemotherapy, cisplatin 75 mg/m2 on day 5, and HIPEC one month after surgery. It was repeated at 3 weeks intervals and at least two cycles administered. RESULTS: A total of 181 cycles of chemotherapy were administered (median, 4 cycles). The median disease free survival time of patients was 40.8 months. The median overall survival time was 48.0 months. The one-, two-, and three-year recurrence rates were 14.6%, 26.8%, and 46.3%, respectively. The main relapse patterns were remnant GC and metastases of retroperitoneal lymph nodes. The morbidity of grade 3 and 4 toxicities of myelosuppression, nausea/ vomiting were less than 10%. The side effects of grade 1 and 2 of hematologic toxicity, nausea and vomiting, abnormal function of liver, kidney or cardiac, fatigue and neurotoxicity were well tolerated. CONCLUSIONS: Cisplatin HIPEC combined with paclitaxel, 5-fluorouracil, and leucovorin intravenous chemotherapy regimen could improve the survival rate and decrease the postoperative recurrence of locally advanced GC.