Novel podophyllotoxin and benzothiazole derivative induces transitional morphological and functional changes in HaCaT cells

Podophyllotoxin (PPT) is an antimitotic drug used topically in the treatment of anogenital warts. Due to its toxicity it cannot be administered systemically as an anticancer agent. However, modified PPT derivatives such as etoposide and teniposide are used clinically as systemic agents. Thus, we invented novel PPT derivative KL3 that was synthesized by photocyclization. Earlier we have shown that KL3 has an anticancer effect in various cell lines. Here we compared the toxicity of KL3 vs PPT on non-cancerous normal human keratinocytes (HaCaT) and peripheral blood mononuclear cells (PBMC) showing that KL3 is less toxic than PPT to non-cancerous cells. At concentrations that neither induced cell death, nor affected cell cycle, KL3 in HaCaT cells evoked transient ultrastructural features of ER stress, swelling of mitochondria and elongation of cytoplasmic processes. Those changes partially reversed with prolonged incubation while features of autophagy were induced. PPT in equivalent concentrations induced HaCaT cell death by cell cycle arrest, intrinsic apoptosis and finally disintegration of cell membranes followed by secondary necrosis. In conclusion, we show that the KL3 derivative of PPT in contrast to PPT allows repair of normal keratinocytes and triggers mechanisms that restore non-tumor cell homeostasis •Podophyllotoxin is too toxic for systemic cancer treatment•The aim of this study was to characterize safety of KL3 to non-cancerous cells•A novel KL3 compound is a derivative of podophyllotoxin containing anticancer benzothiazole group.•KL3 at 1 μM does not induce necrosis nor apoptosis in HaCaT keratinocytes.•HaCaT treated with KL3 1 µM show transient swelling of mitochondria, elongation of cellular protrusions and ER stress.•KL3 at 1 µM allowed recovery of non-tumor cells thus minimizing toxic effects of KL3.