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

Our plain-English summary of Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin, by Y. Shi, E. Felley-Bosco, T.M. Marti, et al (BMC Cancer, 2012).

The study

• Authors: Y. Shi, E. Felley-Bosco, T.M. Marti, K. Orlowski, M. Pruschy, R.A. Stahel
• Journal: BMC Cancer
• Published: 2012;12:571
• Cited by: 102 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Optimizing 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.

Methods: The 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.

Results: We 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.

Conclusion: In 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.

In plain English

This laboratory study tested whether starvation changes the effect of the chemotherapy drug cisplatin in cells and mice. It did not study asbestos exposure or people. The authors grew human cancer cells, including mesothelioma ZL55 cells, and normal mesothelial cells with or without the usual medium supplements, including serum. In ZL55 cells, serum starvation plus cisplatin reduced colony formation more than either treatment alone. In normal SDM104 cells kept in serum, cisplatin reduced survival by 74% compared with untreated cells. Serum-starved SDM104 cells given cisplatin had 55% lower survival than untreated cells, similar to starvation alone. The authors also fasted mice carrying human tumors around each weekly cisplatin injection. Complete remission occurred in 60% of combination-treated mice with mesothelioma tumors (groups of five) and in 40% with lung adenocarcinoma tumors. The article lists six mice per lung-tumor group without explaining how 40% fits. No other group had complete remission. The authors concluded that short-term fasting may enhance the efficacy of cisplatin-based chemotherapy. They noted that the mouse study could not show whether mechanisms seen in cells operate in animals.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: cell culture experiments and mouse tumor xenograft experiments
• Who was studied: Human cell lines: mesothelioma ZL55, lung carcinoma A549, colorectal carcinoma HCT116 with and without p53, and primary normal human mesothelial SDM104 cells. Female nude mice carrying ZL55 tumors (5 per group in the growth curves) or A549 tumors (6 per group in the growth curves).
• Exposure: Cells normally grew in medium supplemented with 15% FCS (serum), EGF and hydrocortisone. For serum starvation they were placed in the same medium without these supplements. Cells received cisplatin (CDDP), 8 μM for 16 hours. Mice received cisplatin 3 mg/kg injected into the abdomen once per week for three weeks. They were fasted from 32 hours before to 16 hours after each injection, with water allowed. No asbestos exposure was studied.
• Main results:
  • In ZL55 mesothelioma cells, the fraction of cells in S-phase (copying DNA) fell by 40% after 24 hours of serum starvation compared with untreated control cells.
  • In ZL55 cells, serum starvation caused a five-fold increase in nuclei positive for activated (phosphorylated) ATM compared with untreated control cells.
  • In HCT116 colorectal cancer cells, serum starvation combined with cisplatin further decreased colony formation in cells with p53. It did not do so in cells lacking p53.
  • In normal SDM104 mesothelial cells kept in serum, cisplatin reduced survival by 74% compared with untreated control cells. In serum-starved SDM104 cells exposed to cisplatin, survival was reduced by 55% compared with untreated control cells, which was similar to the reduction from serum starvation alone.
  • In mice with ZL55 mesothelioma tumors (5 per group), cisplatin alone gave no significant inhibition of tumor growth. Complete remission was seen in 60% of animals given fasting plus cisplatin.
  • In mice with A549 lung adenocarcinoma tumors, fasting plus cisplatin reduced tumor burden by 65% three weeks after treatment. Complete remission without recurrence occurred in 40% of combination-treated animals. The growth-curve figure lists six animals per group, which does not match 40% as a whole number of animals.
  • Mice lost 15% of average body weight during fasting and regained most of it the next day.
• The authors' conclusion: The authors concluded that short-term food starvation may enhance the efficacy of cisplatin-based chemotherapy.
• Limitations the authors state:
  • The authors stated that the design of the mouse study does not allow the conclusion that the mechanisms seen in cells also operate in animals.
  • The authors stated that how serum starvation activates ATM in cancer cells was beyond the scope of this study.

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Chemotherapy, Mesothelioma, Carcinoma.

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