Acetyl-macrocalin B suppresses tumor growth in esophageal squamous cell carcinoma and exhibits synergistic anti-cancer effects with the Chk1/2 inhibitor AZD7762.

Natural products derived from herbal medicines have become a major focus of anti-cancer drug discovery studies. Acetyl-macrocalin B (A-macB) is an ent-diterpenoid isolated from Isodon silvatica. This study aimed to examine the effect and molecular action of A-macB in esophageal squamous cell carcinoma (ESCC) and explore possible drug synergistic modalities. A-macB induced cellular reactive oxygen species (ROS) generation, initiated the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and triggered the caspase-9-dependent apoptosis cascade in ESCC cells. The ROS scavenger N-acetylcysteine (NAC) and the specific p38 inhibitor SB203580 reversed the effects of A-macB on the p38 network and thus rescued ESCC cells from apoptosis. The cellular ROS increase was at least partially due to the suppression of glutathione-S-transferase P1 (GSTP1) by A-macB. A-macB also upregulated the Chk1/Chk2-Cdc25C/Cdc2/Cyclin B1 axis to induce G2/M phase arrest. The cell growth inhibition induced by A-macB was further enhanced by AZD7762, a specific Chk1/Chk2 inhibitor, with a combination index (CI) of <1. Moreover, A-macB efficiently suppressed xenograft growth without inducing significant toxicity, and AZD7762 potentiated the effects of A-macB in the suppression of tumor growth in vivo. Taken together, A-macB is a promising lead compound for ESCC and exerts synergistic anti-cancer effects with AZD7762.

Acetyl-macrocalin B, an ent-kaurane diterpenoid, initiates apoptosis through the ROS-p38-caspase 9-dependent pathway and induces G2/M phase arrest via the Chk1/2-Cdc25C-Cdc2/cyclin B axis in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, and novel effective drugs against NSCLC are urgently needed. Isodon species are rich in ent-kaurane diterpenoids that have been reported to have antitumor bioactivity. Acetyl-macrocalin B (A-macB) is a novel ent-kaurane diterpenoid isolated from Isodon silvatica, and its antitumor efficacy against NSCLC and the underlying mechanisms were scrutinized in depth. The viability of cells treated with A-macB was detected by CCK-8 and colony formation assays. Apoptosis and cell cycle distribution were analyzed by flow cytometry. The mechanisms were investigated by detecting ROS and performing western blotting and verification experiments with specific inhibitors. The in vivo effect of A-macB was explored in a nude mouse xenograft model. A-macB effectively inhibited H1299 and A549 cell viability, triggered apoptosis and delayed cells in the G2/M phase. A-macB induced cellular ROS production and then activated the p38 MAPK-mediated, caspase 9-dependent apoptotic pathway. Both the ROS scavenger NAC and the specific p38 inhibitor SB203580 inactivated the function of p38 induced by A-macB, thus preventing cells from apoptosis. A-macB activated the Chk1/2-Cdc25C-Cdc2/cyclin B1 axis to induce G2/M phase arrest. AZD7762 abrogated the function of Chk1/2, abolished the G2/M delay and enhanced the cytotoxicity of A-macB. Moreover, A-macB efficiently suppressed tumor growth in a mouse xenograft model without noticeable toxicity to normal tissues. Having both efficacy and relative safety, A-macB is a potential lead compound that is worthy of further exploration for development as an anticancer agent.

Long-term outcomes of 307 patients after complete thymoma resection.

BACKGROUND: Thymoma is an uncommon tumor without a widely accepted standard care to date. We aimed to investigate the clinicopathologic variables of patients with thymoma and identify possible predictors of survival and recurrence after initial resection. METHODS: We retrospectively selected 307 patients with thymoma who underwent complete resection at the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China) between January 2003 and December 2014. The associations of patients' clinical characteristics with prognosis were estimated using Cox regression and Kaplan-Meier survival analyses. RESULTS: During follow-up (median, 86 months; range, 24-160 months), the 5- and 10-year disease-free survival (DFS) rates were 84.0% and 73.0%, respectively, and the 5- and 10-year overall survival (OS) rates were 91.0% and 74.0%, respectively. Masaoka stage (P < 0.001), World Health Organization (WHO) histological classification (P < 0.001), and postoperative radiotherapy after initial resection (P = 0.006) were associated with recurrence (52/307, 16.9%). Multivariate analysis revealed that, after initial resection, WHO histological classification and Masaoka stage were independent predictors of DFS and OS. The pleura (25/52, 48.0%) were the most common site of recurrence, and locoregional recurrence (41/52, 79.0%) was the most common recurrence pattern. The recurrence pattern was an independent predictor of post-recurrence survival. Patients with recurrent thymoma who underwent repeated resection had increased post-recurrence survival rates compared with those who underwent therapies other than surgery (P = 0.017). CONCLUSIONS: Masaoka stage and WHO histological classification were independent prognostic factors of thymoma after initial complete resection. The recurrence pattern was an independent predictor of post-recurrence survival. Locoregional recurrence and repeated resection of the recurrent tumor were associated with favorable prognosis.

Prognostic value of preoperative neutrophil-lymphocyte ratio is superior to platelet-lymphocyte ratio for survival in patients who underwent complete resection of thymic carcinoma.

BACKGROUND: Preoperative neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have prognostic value in patients with various operable tumors. The aim of our study was to determine whether NLR and PLR are predictive of survival in thymic carcinoma patients after complete resection. METHODS: A total of seventy-nine patients who underwent complete resection of thymic carcinoma at our hospital between January 2005 and December 2015 were retrospectively enrolled. Differential leukocyte counts were collected before surgery, and the relationships of NLR, PLR, and other patient clinical variables with survival were estimated by Cox regression analysis and Kaplan-Meier survival analysis. RESULTS: Univariate analysis found that a high level of NLR was associated with lower disease-free survival (DFS) (HR: 3.385, 95% CI: 1.073-10.678, P=0.037) and lower overall survival (OS) (HR: 12.836, 95% CI: 1.615-101.990, P=0.016). The optimal NLR threshold of 4.1 could stratify the patients with high risk of recurrence or metastasis (P=0.026) and death (P=0.006). Meanwhile, the NLR value of >4.1 in those patients was associated with bigger tumor size (P=0.035) and more advanced Masaoka stages (P=0.040) compared with NLR ≤4.1. However, the PLR and other variables were not significantly associated with survival in thymic carcinoma patients. CONCLUSIONS: The preoperative NLR of >4.1 was significantly associated with larger tumor size, more advanced Masaoka stages and reduced DFS and OS, but was not an independent predictor of survival in thymic carcinoma patients after complete resection.

Prognostic value of preoperative serum lactate dehydrogenase in thymic carcinoma.

BACKGROUND: The prognostic value of serum lactate dehydrogenase (LDH) has been demonstrated in various solid tumors. We attempted to determine whether serum LDH was predictive of survival in thymic carcinoma after surgical resection. METHODS: Ninety-five patients with thymic carcinoma treated in our hospital between January 2005 and December 2015 were retrospectively enrolled. Serum LDH was measured before surgery and categorized as low or high relative to the upper limit of normal (ULN) (225 U/L). The relationships of serum LDH level and other clinical variables with survival were estimated by Cox regression and Kaplan-Meier survival analysis. RESULTS: Serum LDH levels were found to be significantly associated with overall survival (OS) and progression-free survival (PFS) of these patients. The 1-, 3-, and 5-year PFS were 76%, 51%, and 38%, and the 1-, 3- and 5-year OS were 97%, 75%, and 46%, respectively. Univariate analysis found that high serum LDH (>225 U/L) was associated with both lower OS [hazard ratio (HR) =2.710; 95% confidence interval (CI): 1.363-1.5.391; P=0.004] and PFS (HR =3.365; 95% CI: 1.776-6.374; P<0.001). Multivariate analysis found that high serum LDH was associated with lower PFS (HR =2.122; 95% CI: 1.056-4.267; P=0.035). Moreover, high LDH was significantly associated with advanced Masaoka stage (P=0.001). CONCLUSIONS: High serum LDH (>225 U/L) was an independent predictor of decreased PFS in thymic carcinoma patients. It was also significantly associated with reduced OS, but was not an independent predictor of death in those patients.

Comparative study of video-assisted thoracic surgery versus open thymectomy for thymoma in one single center.

BACKGROUND: Due to the popularity of video-assisted thoracic surgery (VATS) techniques in clinical, thymoma patients via VATS thymectomy are increasing rapidly. However, compared with open thymectomy, the potential superiorities and defects of VATS thymectomy remain controversial. METHODS: A number of 129 patients who underwent thymectomy of early stage thymoma (Masaoka stage I and stage II) in one single center from January 2007 to September 2013 were selected in this retrospective study. Of those patients, 38 thymoma patients underwent VATS thymectomy (VATS group) and 91 underwent open thymectomy (open group) via either transsternal [44] or transthoracic approach [47] in the same period. The postoperative variables, which included postoperative hospital length of stay (LOS), the intensive care unit (ICU) LOS, the entire resection ratio, the number of thoracic drainage tubes, the quantity of output and duration of drainage, were analyzed. Meanwhile, the operation time and blood loss were considered as intraoperative variables. RESULTS: All thymoma patients in the analysis included 19 thymoma patients with myasthenia gravis, among which five patients via VATS thymectomy and 14 patients via open thymectomy respectively. There was no death or morbidity due to the surgical procedures perioperatively. The ICU LOS, operation time, entire resection ratio, and the number of chest tubes were not significantly different in two groups. The postoperative hospital LOS of VATS thymectomy was shorter than that of open thymectomy (5.26 versus 8.32 days, P<0.001). The blood loss of VATS thymectomy was less than open thymectomy (114.74 versus 194.51 mL, P=0.002). Postoperatively, the quantity of chest tubes output in VATS group was less than that in open thymectomy group (617.86 versus 850.08 mL, P=0.007) and duration of drainage in VATS group was shorter than that in open thymectomy group (3.87 versus 5.22 days, P<0.001). CONCLUSIONS: VATS thymectomy is a safe and practicable treatment for early-stage thymoma patients. Thymoma according with Masaoka staging I-II without evident invading seems to be performed through VATS approach appropriately, which has shorter postoperative hospital LOS, less blood loss and less restrictions to activities, hence patients will recover sooner.