Chloroquine enhances the cytotoxicity of topotecan by inhibiting autophagy in lung cancer cells

Although the anti-malaria drug chloroquine(CQ) has been shown to enhance chemotherapy and radiation sensitivity in clinical trials,the potential mechanisms underlying this enhancement are still unclear.Here,we examined the relevant mechanisms by which the multipotent CQ enhanced the cytotoxicity of topotecan(TPT).The lung cancer cell line A549 was treated with TPT alone or TPT combined with CQ at non-cytotoxic concentrations.Cell viability was assessed using the MTT assay.The percentage of apoptotic cells and the presence of a side population of cells were both determined by flow cytometry.Autophagy and the expression of Bcl-2 family proteins were examined by Western blotting.The accumulation of YFP-LC3 dots and the formation of acidic vesicular organelles were examined by confocal microscopy.CQ sensitized A549 cells to TPT and enhanced TPT-induced apoptosis in a Bcl-2 family protein-independent fashion.CQ inhibited TPT-induced autophagy,which modified the cytotoxicity of TPT.However,CQ failed to modify the transfer of TPT across the cytoplasmic membrane and did not increase lysosomal permeability.This study showed that CQ at non-cytotoxic concentrations potentiated the cytotoxicity of TPT by interfering with autophagy,implying that CQ has significant potential as a chemotherapeutic enhancer.

The absence of the ERBB4 hotspot mutations in melanomas in patients from southern China

V-erb-a erythroblastic leukemia viral oncogene homolog 4(ERBB4) has been reported to be somatically mutated in 19% of melanoma cases.To investigate the prevalence of ERBB4 mutations in melanoma patients from southern China,we analyzed 117 formalin-fixed,paraffin-embedded melanoma samples archived in the Sun Yat-sen University Cancer Center.A matrix-assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF MS) platform was used to screen for mutations.No ERBB4 hotspot mutations were detected.Our results indicate that ERBB4 mutations may play a limited role in melanomas in China;therefore,targeting the ERBB4 mutation in melanoma patients from southern China may not be a promising strategy.

Mast Cells in Adjacent Normal Colon Mucosa rather than Those in Invasive Margin are Related to Progression of Colon Cancer

Objective: Mast cells (MC) reside in the mucosa of the digestive tract as the first line against bacteria and toxins. Clinical evidence has implied that the infiltration of mast cells in colorectal cancers is related to malignant phenotypes and a poor prognosis. This study compared the role of mast cells in adjacent normal colon mucosa and in the invasive margin during the progression of colon cancer. Methods: Specimens were obtained from 39 patients with colon adenomas and 155 patients with colon cancers treated at the Sun Yat-sen University Cancer Center between January 1999 and July 2004. The density of mast cells was scored by an immunohistochemical assay. The pattern of mast cell distribution and its relationship with clinicopathologic parameters and 5-year survival were analyzed. Results: The majority of mast cells were located in the adjacent normal colon mucosa, followed by the invasive margin and least in the cancer stroma. Mast cell count in adjacent normal colon mucosa (MCCadjacent) was associated with pathologic classification, distant metastases and hepatic metastases, although it was not a prognostic factor. In contrast, mast cell count in the invasive margin (MCCinvasive) was associated with neither the clinicopathlogic parameters nor overall survival. Conclusion: Mast cells in the adjacent normal colon mucosa were related to the progression of colon cancer, suggesting that mast cells might modulate tumor progression via a long-distance mechanism.