Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin

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.

Δ2-Troglitazone promotes cytostatic rather than pro-apoptotic effects in breast cancer cells cultured in high serum conditions

“…This is in accordance with studies suggesting that serum starvation, as well as short-term starvation (glucose and serum restriction), enhanced the action of diverse chemotherapeutic agents in various cancer cells. 6,44 mTOR pathway could be involved in this process since it is inhibited in low serum conditions and mTOR inhibitors like rapamycin sensitize cancer cells to anticancer drugs. 45,46 Then, it could be on purpose to test the potentiating effect of the co-treatment rapamycin/D2-TGZ on breast cancer cells.…”

Autophagy in blood cancers: biological role and therapeutic implications

“…[95][96][97][98] Importantly, while healthy cells adapt to starvation by reverting to a self-protection mode, cancer cells appear to be less efficient at responding to starvation, possibly due to the aberrant activation of growthpromoting signaling cascades. 71,72,99 In fact, starved cancer cells become even more prone to oxidative stress and more sensitive to chemo-radiotherapy. 71,72 Noticeably, the benefits of short-term starvation in chemoprotection and in the delay of tumor progression are well supported on a pre-clinical level and are also suggested by initial clinical observations.…”

AMP-activated protein kinase (AMPK) beyond metabolism

“…These events have also been linked to AMPK activation. [81][82][83] The topoisomerase II inhibitor etoposide, which mediates DNA breaks by preventing re-ligation of DNA, was shown to induce ATM-dependent activation of AMPK which enhances apoptosis in prostate cancer cells compared with cells lacking functional LKB1-AMPK. 81 In addition, cisplatin, which causes DNA damage by forming intra-strand crosslinks, has been reported to activate the ATM-AMPK network in multiple tumor types.…”