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It is now believed that cancer stem cells (CSCs) that are resistant to chemotherapy due to their undifferentiated nature drive tumor growth, metastasis and relapse, so development of drugs that induce differentiation of CSCs should have a profound impact on cancer eradication. In this study, we screened medicines that are already in clinical use for drugs that induce differentiation of CSCs. We used MDA-MB-231, a human breast cancer cell line that contains cancer stem cell-like cells. We found that acetaminophen, an anti-inflammatory, antipyretic and analgesic drug, induces differentiation of MDA-MB-231 cells. Differentiation was assessed by observing alterations in cell shape and expression of differentiated and undifferentiated cell markers, a decrease in cell invasion activity and an increase in susceptibility to anti-tumor drugs. This increased susceptibility seems to involve suppression of expression of multidrug efflux pumps. We also suggest that this induction of differentiation is mediated by inhibition of a Wnt/β-catenin canonical signaling pathway. Treatment of MDA-MB-231 cells with acetaminophen in vitro resulted in the loss of their tumorigenic ability in nude mice. Furthermore, administration of acetaminophen inhibited the growth of tumor xenografts of MDA-MB-231 cells in both the presence and absence of simultaneous administration of doxorubicine, a typical anti-tumor drug for breast cancer. Analysis with various acetaminophen derivatives revealed that o-acetamidophenol has a similar differentiation-inducing activity and a similar inhibitory effect on tumor xenograft growth. These results suggest that acetaminophen may be beneficial for breast cancer chemotherapy by inducing the differentiation of CSCs.

The expression of heat shock proteins (HSPs), particularly HSP70, provides resistance to stressors. We recently reported that ultraviolet (UV)-induced melanin production and skin damage were suppressed in transgenic mice expressing HSP70 and that an extract of Eupatorium lindleyanum induces the expression of HSP70 in cells. Here we report the purification of eupalinolide A and B (EA and EB) from E. lindleyanum, and describe their actions as HSP-inducers. EA and EB both induced the expression of HSP70 in cells at concentrations that did not significantly affect cell viability. Treatment of cells with EA or EB activated heat shock factor 1 (HSF1), while the artificial suppression of HSF1 expression diminished the EA- or EB-mediated induction of HSP70 expression. Furthermore, EB inhibited the interaction between HSF1 and HSP90, which is known to inhibit the activity of HSF1. These findings suggest that EA and EB induce the expression of HSP70 via the activation of HSF1 by inhibiting the interaction between HSF1 and HSP90. EA and EB both induced the expression of HSP70 synergistically with other stressors. Furthermore, pre-treatment of cells with EA or EB suppressed melanin production and stressor-induced apoptosis. These effects were suppressed by the artificial suppression of HSP70 expression. In vivo, the percutaneous administration of EB induced the expression of HSP70 and suppressed UVB radiation-induced damage, inflammatory responses and melanin production in the skin. These results suggest that EA and EB could be beneficial for use in cosmetics and medicines as a consequence of their inhibitory action on UV-induced skin damage and melanin production.

A major clinical problem encountered with the use of non-steroidal anti-inflammatory drugs (NSAIDs), is gastrointestinal complications. We previously reported that NSAIDs induce both necrosis and apoptosis in vitro. We here examined the cyclooxygenase (COX) dependency of this cytotoxic effect of NSAIDs and its involvement in NSAID-induced gastric lesions. Necrosis and apoptosis by NSAIDs was observed with all selective COX-2 inhibitors except rofecoxib and was not inhibited by exogenously added prostaglandin E2, suggesting that cytotoxicity of NSAIDs seems to be independent of the inhibition of COX. Intravenously administered indomethacin, which completely inhibited COX activity at gastric mucosa, did not produce gastric lesions. Orally administered selective COX-2 inhibitors, which did not inhibit COX at gastric mucosa, also did not produce gastric lesions. Interestingly, a combination of the oral administration of each of all selective COX-2 inhibitors except rofecoxib with the intravenous administration of indomethacin clearly produced gastric lesions. These results suggest that in addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs may be involved in NSAID-induced gastric lesions.