Bioactive 3,4-seco-Triterpenoids from the Fruits of Acanthopanax sessiliflorus

Eight new 3,4-seco-lupane triterpenes and glycosides, acanthosessiligenins I and II (1, 3) and acanthosessiliosides A-F (2, 4-8), as well as six known 3,4-seco-lupane triterpenes (9-14) were isolated from an ethanolic extract of Acanthopanax sessiliflorus fruits. The chemical structures of 1-8 were determined by spectroscopic data interpretation. All isolated compounds were tested for their cytotoxicity against six human cancer cell lines and their ability to inhibit LPS-induced nitric oxide production in RAW 264.7 macrophages.     

Standardized flavonoid-rich fraction of Artemisia princeps Pampanini cv. Sajabal induces apoptosis via mitochondrial pathway in human cervical cancer HeLa cells

Ethnopharmacological relevance

Artemisia princeps Pampanini is widely used in Eastern traditional medicine for the treatment of circulatory disorders, such as, dysmenorrhea, hematuria, hemorrhoids, and inflammation, and is also used to treat chronic conditions, such as, cancers, ulcers, and digestive disorders.

Aim of the study

The purpose of this study is to investigate the effect of a standardized flavonoid-rich fraction of Artemisia princeps Pampanini cv. Sajabal (FRAP) on the induction of apoptosis and the molecular mechanism involved in human cervical cancer HeLa cells.

Materials and methods

Human cervical cancer HeLa cells were treated with FRAP and apoptosis was detected by cell morphologic observation, annexin-V-PI staning and western blot analysis on the expression of protein associated with cell death.

Results

FRAP led to the cleavages of caspase-3, -8, and -9 and the cleavage of poly (ADP-ribose) polymerase (PARP) in HeLa cells. Caspase-3 inhibitor (z-DEVD-fmk), caspase-8 inhibitor (z-IETD-fmk), caspase-9 inhibitor (z-LEHD), and broad caspase inhibitor (z-VAD-fmk) significantly suppressed the FRAP-induced accumulation of annexin V positive cells. Furthermore, it was found that FRAP caused a loss of mitochondrial membrane potential (MMP) and the release of cytochrome c to the cytosol. Furthermore, the overexpression of Bcl-xL significantly prevented FRAP-induced apoptosis, MMP changes, and the activations of caspase-3, -8, and -9. Interestingly, pretreatment with caspase-8 inhibitor significantly reduced the FRAP-induced activation of caspase-3 but not that of caspase-9, whereas the caspase-3 inhibitor, z-DEVD-fmk, markedly attenuated the FRAP-induced activation of caspase-8. In BALB/c^nu/nu mice bearing a HeLa xenograft, FRAP dosed at 25 or 50 mg/kg significantly inhibited tumor growth.

Conclusion

Our results indicate caspase-mediated activation of the mitochondrial death pathway plays a critical role in the FRAP-induced apoptosis of HeLa cells and that FRAP inhibits the in vivo tumor growth of HeLa xenograft mice.     

A risk stratification by hormonal receptors (ER, PgR) and HER-2 status in small (≤1 cm) invasive breast cancer: who might be possible candidates for adjuvant treatment?

As the use of screening mammography expands, the proportion of invasive breast cancer ≤1 cm is increasing. The aims of this study were: (1) to identify risk factors for systemic metastases in patients with ≤1 cm invasive breast cancer and (2) to investigate the patient groups at the greatest risk for metastases with such small tumors. Data were collected retrospectively from the breast cancer registry of our institution for patients with invasive breast cancer from October 1994 to December 2004. Of 4,036 patients who received curative breast cancer surgery, we identified 427 patients who had T1a or T1b breast cancer excluding 39 patients who received neoadjuvant chemotherapy. Ipsilateral axillary lymph node involvement was found in 13% (57/427) of patients at the time of surgery. A multivariate analysis was conducted in 370 (T1aN0, T1bN0) patients without lymph node involvement. In a Cox-regression model, HER-2 positive and triple negative (TN) groups were identified as independent risk factors to predict distant relapse-free survival (DRFS) [Hazard ratio (HR) 8.8, P = 0.003 for HER-2 positive group; HR 5.1, P = 0.026 for TN group] in T1bN0 tumors. Statistical significance was not maintained when the analysis was limited to T1aN0 tumors. Even though T1aN0 and T1bN0 tumors have a relatively low risk of systemic failure, anti-HER-2-directed therapy for HER-2 group and new innovative adjuvant systemic treatment for TNBC patients with T1bN0 tumors should be considered. Prospective adjuvant trials are warranted in these subgroups of patients.     

Overexpression of stathmin1 in the diffuse type of gastric cancer and its roles in proliferation and migration of gastric cancer cells

Background:

Stathmin1 is a microtubule-regulating protein that has an important role in the assembly and disassembly of the mitotic spindle. The roles of stathmin1 in carcinogenesis of various cancers, including prostate and breast cancer, have been explored. However, its expression and roles in gastric cancer have not yet been described.

Methods:

Stathmin1 expression in paraffin-embedded tissue sections from 226 patients was analysed by immunohistochemistry. Roles of stathmin1 were studied using a specific small interfering RNA (siRNA).

Results:

The expression of stathmin1 was positively correlated with lymph node metastasis, TNM stages and vascular invasion, and negatively with recurrence-free survival, in the diffuse type of gastric cancer. The median recurrence-free survival in patients with a negative and positive expression of stathmin1 was 17.0 and 7.0 months, respectively (P=0.009). When the expression of stathmin1 was knocked down using siRNA, the proliferation, migration and invasion of poorly differentiated gastric cancer cells in vitro were significantly inhibited. Moreover, stathmin1 siRNA transfection significantly slowed the growth of xenografts in nude mice.

Conclusion:

These results suggest that stathmin1 can be a good prognostic factor for recurrence-free survival rate and is a therapeutic target in diffuse-type gastric cancer.     

Multicenter phase 2 study of belotecan,a new camptothecin analog,and cisplatin for chemotherapy‐naive patients with extensive‐disease small cell lung cancer

BACKGROUND:

The objective of this study was to investigate the efficacy of belotecan, a new camptothecin analog, combined with cisplatin for the treatment of chemotherapy‐naive patients with extensive‐disease small cell lung cancer (ED SCLC).

METHODS:

Treatment consisted of belotecan 0.5 mg/m² daily on Days 1 through 4 and cisplatin 60 mg/m² on Day 1 of a 3‐week cycle for up to 6 cycles unless there was disease progression, unacceptable toxicity, or patient refusal. Response assessment was done every 2 cycles using the Response Evaluation Criteria in Solid Tumors, and toxicity assessment was done every cycle using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.

RESULTS:

Between September 2006 and March 2008, 30 patients participated in the study. Among them, 21 patients achieved a partial response, and the response rate was 70% (95% confidence interval [CI], 50.6%‐85.3%); and, after a median follow‐up of 20.2 months, the median progression‐free survival was 6.9 months (95% CI, 6.3‐7.5 months), and the overall survival was 19.2 months (95% CI, 13.3‐25.2 months). Grade 3 and 4 adverse events included neutropenia in 23 patients, thrombocytopenia in 8 patients, febrile neutropenia in 9 patients, nausea in 3 patients, and pneumonia in 3 patients. There was 1 treatment‐related death from pneumonia. However, nonhematologic toxicity generally was mild and manageable.

CONCLUSIONS:

The belotecan and cisplatin combination that was studied demonstrated promising response rates and survival outcomes with a manageable toxicity profile for chemotherapy‐naive patients who had ED SCLC. The authors concluded that the combination warrants further randomized trials. Cancer 2010. © 2010 American Cancer Society.