Although single targeted anti-
cancer drugs are envisaged as safer treatments because they do not affect normal cells,
cancer is a very complex disease to be eradicated with a single targeted
drug. Alternatively, multi-targeted drugs may be more effective and the
tumor cells may be less prone to develop drug resistance although these drugs may be less specific for
cancer cells. We have previously developed a new strategy to endow human
pancreatic ribonuclease with antitumor action by introducing in its sequence a non-classical
nuclear localization signal. These engineered
proteins cleave multiple species of
nuclear RNA promoting apoptosis of
tumor cells. Interestingly, these
enzymes, on
ovarian cancer cells, affect the expression of multiple genes implicated in metabolic and signaling pathways that are critic for the development of
cancer. Since most of these targeted pathways are not highly relevant for non-proliferating cells, we envisioned the possibility that nuclear directed-
ribonucleases were specific for
tumor cells. Here, we show that these
enzymes are much more cytotoxic for
tumor cells in vitro. Although the mechanism of selectivity of NLSPE5 is not fully understood, herein we show that p27KIP1 displays an important role on the higher resistance of non-
tumor cells to these
ribonucleases.