A novel 7-bromoindirubin with potent anticancer activity suppresses survival of human melanoma cells associated with inhibition of STAT3 and Akt signaling

STAT3 and Akt signaling have been validated as potential molecular targets for treatment of cancers including melanoma. These small molecule inhibitors of STAT3 or Akt signaling are promising for developing anti-melanoma therapeutic agents. MLS-2438, a novel 7-bromoindirubin, a derivative of the natural product indirubin, was synthesized with a bromo-group at the 7-position on one indole ring and a hydrophilic group at the 3′-position on the other indole ring. We tested the anticancer activity of MLS-2438 and investigated its mechanism of action in human melanoma cell lines. Here, we show that MLS-2438 inhibits viability and induces apoptosis of human melanoma cells associated with inhibition of STAT3 and Akt signaling. Several pro-apoptotic Bcl-2 family proteins are involved in the MLS-2438 mediated apoptosis. MLS-2438 inhibits Src kinase activity in vitro and phosphorylation of JAK2, Src, STAT3 and Akt in cultured cancer cells. In contrast to the decreased phosphorylation levels of JAK2, Src, STAT3 and Akt, phosphorylation levels of the MAPK (Erk1/2) signaling protein were not reduced in cells treated with MLS-2438. These results demonstrate that MLS-2438, a novel natural product derivative, is a Src inhibitor and potentially regulates kinase activity of JAK2 and Akt in cancer cells. Importantly, MLS-2438 suppressed tumor growth with low toxicity in a mouse xenograft model of human melanoma. Our findings support further development of MLS-2438 as a potential small-molecule therapeutic agent that targets both STAT3 and Akt signaling in human melanoma cells.     

Radical radiotherapy for nasopharyngeal carcinoma in elderly patients: the importance of co-morbidity assessment

Elderly patients represent a unique challenge for radical treatment in nasopharyngeal carcinoma (NPC) because of age and co-morbid conditions. We sought to evaluate the outcome of this particular group of patients and to identify key factors affecting treatment outcome. From 1998 to 2008, 990 consecutive NPC patients without distant metastasis were treated with radical radiotherapy with planned total dose >66 Gy. Among them, 103 (10.4%) patients were elderly aged >70 (group A). Their clinical characteristics and outcome were compared with those aged <70 (group B). Mortality at 90 days was used as a proxy of early deaths related to treatment. Co-morbidities were measured by the Adult Co-morbidity Evaluation 27 (ACE-27). Group A presented more commonly with poorer performance status. They showed higher rates of acute reaction, radiotherapy incompletion and mortality at 90 days (7.8% vs. 1.2%, p<0.001). The 5-year overall survival rates were 43.9% and 78.1% for groups A and B, respectively (p<0.001). No difference in failure free survival rates was noted. For group A, ACE-27 was the only predicting factor for mortality at 90 days [ACE-27 2-3 vs. 0-1: HR 15.86 (2.68-93.95), p=0.002], and the most important prognostic factors for overall survival included age, presenting stage and ACE-27 (p<0.05). Elderly NPC patients had poorer tolerance to radiotherapy. Early deaths related to treatment were not uncommon. A reasonable disease control can still be attained after radical radiotherapy for those who were able to survive through the peri-radiotherapy period. Patient selection and treatment approach with reference to ACE-27 should be considered.     

Systematic review of pancreaticoduodenectomy for locally advanced gastric cancer

Background

The purpose of this study was to identify and synthesize findings from all articles on surgical and long-term outcomes in patients with gastric cancer undergoing gastrectomy combined with pancreaticoduodenectomy (PD).

Methods

Electronic literature searches were conducted using Medline, EMBASE, and Cochrane databases from January 1, 1985, to December 31, 2009.

Results

Eight retrospective case series were included, with 132 patients having PD combined with gastrectomy. PD was combined with total gastrectomy in 27 patients, and subtotal gastrectomy in 81 patients; 24 patients had undocumented gastric resection type. Clinical stage was available for 92 patients (4 stage I, 7 stage II, 26 stage III, and 55 stage IV). Five studies (98 patients having PD combined with gastrectomy) compared PD and gastrectomy to gastrectomy alone. In the four studies reporting morbidity, PD had a higher morbidity. The pooled pancreatic anastomotic leak rate was 24.5% for the seven studies in which complications were reported; however, there were no peri-operative deaths. Long-term survival (37.3% at 5 years) in gastric cancer patients with PD combined with gastrectomy was described; however, survival was poor in the setting of incurable factors. Due to heterogeneity of patients and staging techniques in the case series no recommendations can be made on the appropriate selection criteria for patients undergoing PD and gastrectomy.

Conclusion

PD for gastric cancer invading the pancreas is associated with a higher morbidity; given the heterogeneous data, defining exact selection criteria is difficult.

     

A systematic review of spleen and pancreas preservation in extended lymphadenectomy for gastric cancer

Background

The overall prognosis and survival of patients with advanced gastric cancer are generally poor. Extended lymphadenectomy is recommended for patients with advanced gastric cancer; however, splenectomy and distal pancreatectomy performed with an extended lymph node dissection may be associated with increased morbidity and mortality.

Method

Electronic literature searches were conducted using Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1 January 1998 to 31 December 2009. Studies on gastric carcinoma investigating extended lymphadenectomy with splenectomy and/or pancreaticosplenectomy that reported data on surgical outcomes or survival were selected.

Results

Forty studies were included in this review. Decreased complication rates were demonstrated with spleen preservation in two prospective studies and three retrospective studies, and with pancreas preservation in five retrospective studies. No randomized controlled trial showed survival benefit or detriment for preservation of spleen or pancreas in extended lymphadenectomy. Improved survival was demonstrated with spleen preservation in two prospective and eight retrospective studies, and with pancreas preservation in one prospective and four retrospective studies.

Conclusions

Preservation of the spleen and pancreas during extended lymphadenectomy for gastric cancer decreases complications with no clear evidence of improvement or detriment to overall survival.