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Anticancer drug-induced tumor suppression may involve mechanisms of protection against neoplastic transformation that are normally latent in mammalian cells and consist in a genetic program implemented during anti-tumoral defense. This defense program results in the self elimination of cells harboring potentially dangerous mutations by triggering cell death through apoptosis and/or autophagy or in the execution of a program that leads to a permanent growth arrest known as senescence. These responses are considered crucial tumor suppressive mechanisms and their study appears to be essential to develop therapeutical procedures based on the enhancement of the different responses. This review summarizes fundamental knowledge on the underlying mechanisms able to limit excessive or aberrant cellular proliferation and on the prognostic value of both apoptosis and senescence detection. In addition, interesting evidence showing that different drugs induce senescence or cell death depending on the genetic features of the tumor cells as well as on the integrity of the relative pathways is reported.

Interferon (IFN) was the first cytokine produced by recombinant DNA technology used in wide-spread clinical treatment of infectious diseases as well as malignancies. The IFN clinical potential was clearly realized from the outset. However, IFN represents one of the most controversial drugs of our time, as remarkable cycles of promise and disappointment have affected its development and use. Considerable evidence regarding anti-tumor activities of IFNs has been reported. In this paper we focus on molecular bases of the IFN system that may relate to its antitumor activities. Many of the numerous genes transcriptionally activated by IFNs have been shown to encode proteins that activate immune recognition of tumor cells, directly or indirectly exert tumor suppressor activity and/or control tumor cell cycle and programmed cell death. In addition, a physiological relevant function for endogenous type I IFN in cancer immunoediting process and a new way to IFN clinical use based on gene therapy or vaccine-like approaches have recently been suggested. The identification of selected tissue-specific and/or tumor-specific target pathways as well as of different type I IFN tumor escape and resistance mechanisms may provide novel approaches in the search for new IFN-based therapeutic strategies to circumvent cancer disease or improve clinical outcome. Promising IFN treatment has been recently defined by using novel pharmaceutical preparations with a more favourable pharmacokinetic response, also in combination with other bioreagents or other modalities of therapy. Translational research, linking both basic and clinical research, will lead to a new rationale for the use of IFN in cancer therapy.

Type I Interferon (IFN) and all-trans retinoic acid (RA) inhibit cell proliferation of squamous carcinoma cell lines (SCC). Examinations of growth-affected cell populations show that SCC lines ME-180 and SiHa treated with IFN-beta undergo a specific slower progression through the S phase that seems to trigger cellular death. In combination treatment RA potentiates IFN-beta effect in SCC ME-180 but not in SiHa cell line, partially resistant to RA antiproliferative action. RA added as single agent affects cell proliferation differently by inducing a slight G1 accumulation. The IFN-beta-induced S phase lengthening parallels the increased expression of PML, a nuclear phosphoprotein specifically up-regulated at transcriptional level by IFN, whose overexpression induces cell growth inhibition and tumor suppression. We report that PML up-regulation may account for the alteration of cell cycle progression induced by IFN-beta in SCC by infecting cells with PML-PINCO recombinant retrovirus carrying the PML-3 cDNA under the control of the 5' LTR. In fact PML overexpression reproduces the IFN-beta-induced S phase lengthening. These findings provide important insight into the mechanism of tumor suppressing function of PML and could allow PML to be included in the pathways responsible for IFN-induced cell growth suppression.