Combined effect of aloe-emodin and chemotherapeutic agents on the proliferation of an adherent variant cell line of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) has only limited sensitivity to chemotherapeutic agents. The aim of the study was to determine if members of the anthraquinone family could be used as adjuncts to increase the growth inhibiting effect of anticancer agents in MCC. An adherent variant of MCC was derived from a previously established MCC cell line suspension. Cells were characterized by immunocytochemical methods using specific antibodies against epithelial (low molecular weight cytokeratins and cytokeratin 20) and neuroendocrine (neuron-specific enolase, neurofilament protein, chromogranin A and synaptophysin) antigens. Emodin and aloe-emodin, members of the anthraquinone family, inhibited proliferation of the adherent MCC cells, with a slight advantage of aloe-emodin over emodin. Aloin had no effect on cell proliferation. The chemotherapeutic agents, cis-platinol (abiplastin), doxorubicin (adriablastin), and 5-fluorouracil, and the tyrosine kinase inhibitor STI 571, all independently inhibited the proliferation of adherent MCC cells. The addition of aloe-emodin potentiated their inhibitory effect, especially when low concentrations of the anticancer compounds were used. The antiproliferative action of STI 571 may be associated with the presence of anti-c-kit antibodies. The combined use of anticancer agents, especially at low concentrations, and aloe-emodin may be considered a preferable means for treating MCC.

Variable cytotoxicity of amifostine in malignant and non-malignant cell lines.

Amifostine is the best known radioprotector and chemoprotector which has already been incorporated into general oncology practice. However, the data regarding its action at the cellular level remain unclear. The present study examined the effect of amifostine with and without ionizing radiation on the growth of malignant and non-malignant cell lines. Amifostine was found to have a remarkable cytotoxic effect on malignant epithelial cell lines but a modest cytotoxic effect on malignant melanoma and non-malignant cell lines. It demonstrated an additive effect with radiation therapy on the malignant cell line and a variable effect on the non-malignant cell line. Endothelial cells were not affected by amifostine, but the myoblast cells showed a synergistic effect of amifostine and radiation. These findings demonstrate that the cytotoxic as well as the radioprotective effect of amifostine are cell-specific. Thus, caution should be exercised in the use of amifostine as a radioprotector, and it should be tested for each model of disease.

Basic fibroblast growth factor mediated growth inhibition in breast cancer cells is independent of ras signaling pathway.

Our previous studies have demonstrated that basic fibroblast growth factor (bFGF) inhibits the growth of MCF-7 human breast cancer cells via binding to high affinity cell surface receptors. The downstream signaling of bFGF was reported to involve the ras pathway. The aim of the present study was to examine the bFGF-induced growth inhibition in the presence of lovastatin, a farnesyl transferase inhibitor, which impaired ras signaling by preventing its association with the plasma membrane. We found that the combined cytotoxicity induced by lovastatin and bFGF was greater than the cytotoxicity induced by each agent alone. Similarly, the protein level of P21/WAF1/cip1 was greater after exposure to both agents together, than separately. bFGF did not interfere with the lovastatin-induced inhibition of P21/RAS membrane association, while lovastatin did not prevent MAPK activation by bFGF. Based on these findings we suggest that the growth inhibitory effect of bFGF on breast cancer cells is largely independent of the ras signaling pathway. Understanding these pathways may enable active intervention to alter the therapeutic ratio favorably in the treatment of breast cancer.

The effect of aloe emodin on the proliferation of a new merkel carcinoma cell line.

A free-floating cell line has been established from a metastatic lesion of a Merkel cell carcinoma (MCC) patient. The cell line was characterized by immunocytochemical reactions with antibodies against the epithelial and neuroendocrine antigens: cytokeratin 20, neuron-specific enolase, chromogranin A, neurofilament protein, synaptophysin, and calcitonin. Karyotype analysis of the MCC cells showed deletion in chromosomes 3 and 7, loss of chromosome 10, and several translocations in other chromosomes. No mutation was detected in the TP53 gene, after analyzing the complete coding region. Growth factors such as basic fibroblast growth factor, transforming growth factor-beta, and nerve and epidermal growth factors had no effect on the proliferation of the cells. The differentiation-inducing agents sodium butyrate and dimethyl sulfoxide, especially the former, markedly inhibited the proliferation of the MCC cells. Aloe emodin, a natural constituent of aloe vera leaves, significantly inhibited the growth of MCC cells. Aloe emodin has been reported to be nontoxic for normal cells but to possess specific toxicity for neuroectodermal tumor cells. Differentiation-inducing agents, and aloe emodin, merit further investigation as potential agents for treating MCC.