While numerous studies have evaluated the cell death inducing effect of several flavonoids in cancer cells, the effects of flavonoids on autophagy are poorly documented. However, massive acidic vacuolization was observed upon in vitro treatment of cells with prenylflavonoids, Quercetin and Curcimin. Induction of autophagy by flavonoids or flavonoid-containing multiherbal preparation was seen to induce apoptotic and non-apoptotic, caspase independent celldeath. Moreover, blocking of autophagosome maturation by flavonoids was seen to result in apoptosis recently. Considering these opposite effects, specified research is necessary to unravel the diverse effects of flavonoids on autophagy and apoptosis. We report for the first time the induction of autophagy in a metastatic SCC cell line following treatment with the flavonoid LUT. Furthermore, we assessed the contribution of LUT-dependent autophagy induction to the increased survival of MET4 cells using the lysosomotropic agent chloroquine, which prevents lysosomal degradation. The marked increase of cell death detected upon CQ co-treatment, suggested that addition of a late phase autophagy inhibitor to LUT reduced chemoresistance of metastatic SCC. Notably, addition of 3-MA, an early stage autophagy inhibitor, diminished the improved apoptosis induction by CQ in LUT treated cells, suggesting that accumulation of lysosomes is necessary for the cell death inducing effect of LUT. A different outcome of autophagy inhibition depending on the stage of autophagy inhibition, has been reported earlier in an Imatinib study. The combination of an autophagy inhibitor with agents that induce autophagy in cancer cells as a survival response has been proposed recently as a novel cancer therapeutic strategy. For instance, combination of CQ or hydroxychloroquine with chemotherapy, targeted therapy or radiotherapy is currently under intensive investigation in preclinical as well as clinical trials. Thus, cancer appears to be a promising indication for this old drug CQ, which is widely used as an anti-malarial and anti-rheumatic drug. In summary, different human malignant keratinocyte cell lines treated with LUT showed increased apoptotic cell death, while normal human keratinocytes remained unaffected. In addition, the efficacy of LUT to induce apoptosis appeared to be tumor progression dependent. Whereas primary MET1 tumor cells were very sensitive to AKT-inhibition by LUT, complete inhibition of AKT signaling in metastatic MET4 cells was not sufficient for notable cell death induction. However, LUT induced massive autophagy in MET4 cells, which was paralleled by a vast increase in acidic vacuoles. We showed that simultaneous inhibition of late phase autophagy SB431542 resulted in a sensitization of the resistant MET4-cells to LUT-induced cell death. Altogether, our in vitro data suggest that LUT may provide a therapeutic tool for the treatment of patients with advanced SCC and that resistance may be circumvented by supplementation of autophagy inhibitors, like CQ. Additional studies are MK-0683 warranted to further investigate the therapeutic value and clinical usefulness of LUT.