Anticancer effect of tetrandrine on primary cancer cells isolated from ascites and pleural fluids
Introduction
Malignant effusion is a common and distressing complication of advanced malignant diseases. Approximately half of patients with metastatic cancers develop malignant pleural effusion or ascites at some point, which is likely to cause significant symptoms such as dyspnea and abdominal distention [1]. Tumor spread via survival and proliferation of tumor cells in body cavity fluid is an important route of metastasis and a frequent cause of morbidity in many malignancies. Evacuation of the pleural fluid and prevention of its re-accumulation are the main goals of management. However, optimal treatment is controversial and there is no universally standard approach. Development of novel methods and potent drugs to control malignant pleural effusion should be a high priority in palliative care of cancer patients.
Tetrandrine (TET), a bis-benzylisoquinoline alkaloid isolated from the Chinese herb “Han-Fang-Chi” (Stephania tetrandra S. Moore), has been reported to have many pharmacological effects including anti-inflammation [2], antioxidant [3], antifibrotic [4] and anti-tumor activity [5]. Tetrandrine regulates cellular redox states, which may reduce proliferation and induce apoptosis in tumor cells [6]. It also induces cell cycle arrest in the G1 phase via p53 and the Fas/FasL apoptotic system in HepG2 cells [7]. Furthermore, it has been shown to be a potent inhibitor of P-gp drug efflux and a resistant reversal agent to daunorubicin, vinblastine and doxorubicin in leukemia cells [8]. Our earlier study has demonstrated synergistic interaction between tetrandrine and chemotherapeutic agents in human gastric cancer cell lines [9].
To date, studies demonstrating the anti-tumor activity of tetrandrine have mainly been done with established cell lines. In this study, we report the cytotoxicity effect of tetrandrine on primary cancer cells isolated from ascites and pleural fluid of patients. To elucidate the mechanisms possibly involved, the expression levels of apoptosis associated genes were also determined.
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Cell lines and cell culture
Human gastric cancer cells BGC-823, liver cancer cells SMMC-7721, lung cancer cells A549 and colon cancer cells Lovo were obtained from Shanghai Institute of Cell Biology (Shanghai, China). These cells were grown in RPMI 1640 medium (GIBCO BRL) with 10% fetal bovine serum (FBS) and 100 U/mL penicillin–streptomycin at 37 °C in a water-saturated atmosphere with 5% CO2.
Chemotherapeutic agents
The chemotherapeutic drugs (docetaxel, cisplatin, 5-fluorouracil) used in the assay were obtained as vials for injection and made up
Sensitivity of cancer cells to tetrandrine
We first examined the cytotoxicity of each drug for BGC-823, SMMC-7721, A549 and Lovo cells lines. Table 1 shows the IC50 doses for these four cells following exposure to tetrandrine or chemotherapeutic agents. Consistent with the studies that have been done on established cell lines, we found that a 3-day treatment with 10–40 μM tetrandrine inhibited ≈50% of the cells in several cell lines. The IC50 values of tetrandrine for BGC-823, SMMC-7721, A549 and Lovo cells were 11.20 μM, 21.76 μM, 24.0 μM
Discussion
Effusions may be the presenting sign of malignancy or the first manifestation of recurrence and relapse. Here, we first describe the use of cancer cells isolated from effusions for studying responses to tetrandrine and other anticancer agents used currently in clinical. These primary cancer cells would be a more accurate model for initial drug trails, as they reflect the situation seen in the body. In our studies of the response of primary cancer cells to tetrandrine, we made several
Acknowledgments
This work is supported in part by Health Department in Jiangsu Province (H200640), National Nature Science Foundation of China (30670958) and Medical Technology Development Foundation of Nanjing (ZKX05015).
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These authors contributed equally to this work.