Abstract
BackgroundOptimizing the safety and efficacy of standard chemotherapeutic agents such as cisplatin (CDDP) is of clinical relevance. Serum starvation in vitro and short-term food starvation in vivo both stress cells by the sudden depletion of paracrine growth stimulation.MethodsThe effects of serum starvation on CDDP toxicity were investigated in normal and cancer cells by assessing proliferation, cell cycle distribution and activation of DNA-damage response and of AMPK, and were compared to effects observed in cells grown in serum-containing medium. The effects of short-term food starvation on CDDP chemotherapy were assessed in xenografts-bearing mice and were compared to effects on tumor growth and/or regression determined in mice with no diet alteration.ResultsWe observed that serum starvation in vitro sensitizes cancer cells to CDDP while protecting normal cells. In detail, in normal cells, serum starvation resulted in a complete arrest of cellular proliferation, i.e. depletion of BrdU-incorporation during S-phase and accumulation of the cells in the G0/G1-phase of the cell cycle. Further analysis revealed that proliferation arrest in normal cells is due to p53/p21 activation, which is AMPK-dependent and ATM-independent. In cancer cells, serum starvation also decreased the fraction of S-phase cells but to a minor extent. In contrast to normal cells, serum starvation-induced p53 activation in cancer cells is both AMPK- and ATM-dependent. Combination of CDDP with serum starvation in vitro increased the activation of ATM/Chk2/p53 signaling pathway compared to either treatment alone resulting in an enhanced sensitization of cancer cells to CDDP. Finally, short-term food starvation dramatically increased the sensitivity of human tumor xenografts to cisplatin as indicated not only by a significant growth delay, but also by the induction of complete remission in 60% of the animals bearing mesothelioma xenografts, and in 40% of the animals with lung carcinoma xenografts.ConclusionIn normal cells, serum starvation in vitro induces a cell cycle arrest and protects from CDDP induced toxicity. In contrast, proliferation of cancer cells is only moderately reduced by serum starvation whereas CDDP toxicity is enhanced. The combination of CDDP treatment with short term food starvation improved outcome in vivo. Therefore, starvation has the potential to enhance the therapeutic index of cisplatin-based therapy.
Highlights
Optimizing the safety and efficacy of standard chemotherapeutic agents such as cisplatin (CDDP) is of clinical relevance
Serum starvation sensitizes ZL55cancer cells to CDDP FACS analysis of BrdU pulse-labeled ZL55 cancer cells revealed that the fraction of cells in S-phase were decreased by 40% after 24 hours serum starvation compared to untreated control (Figure 1A-C)
When cancer cells were exposed to CDDP in serum-starved conditions, an increased sensitivity was observed: the combined treatment of CDDP and serum starvation additively reduced the clonogenicity of human mesothelioma ZL55 cells in comparison to either treatment alone (Figure 1D)
Summary
Optimizing the safety and efficacy of standard chemotherapeutic agents such as cisplatin (CDDP) is of clinical relevance. Cisplatin (CDDP) is a standard therapeutic agent for the treatment of various solid tumors. The aim of our investigation was to identify ways to increase the efficacy of CDDP for cancer killing while enhancing the tolerance of normal cells. Therapy targeting the stress response pathways, which can principally be reached through inhibiting the activity of these pathways or through overloading stress to overwhelm these pathways, may be detrimental to cancer cells while sparing normal cells [5]. For example it has been shown that interfering the cellular response to oxidative stress by a small molecule selectively kills cancer cells [6], and that targeting replicative stress response pathway resulted in specific killing of oncogene-driven tumors [7]
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