Dexamethasone alleviates pemetrexed-induced senescence in Non-Small-Cell Lung Cancer

Our plain-English summary of Dexamethasone alleviates pemetrexed-induced senescence in Non-Small-Cell Lung Cancer, by H. Ge, J. Ke, N. Xu, et al (Food and Chemical Toxicology, 2018).

The study

• Authors: H. Ge, J. Ke, N. Xu, H. Li, J. Gong, X. Li, Y. Song, H. Zhu, C. Bai
• Journal: Food and Chemical Toxicology
• Published: 2018;119:86-97
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pemetrexed (PEM) is a novel and multi-targeted antifolate used as an antineoplastic agent for non-small cell lung cancer (NSCLC) and pleural mesothelioma. Although glucocorticoid was often used with PEM to reduce toxicity during the chemotherapy, it is not clear yet whether glucocorticoid co-administration could affect PEM efficacy in NSCLC. Here we established NSCLC cell lines and examined the effects of dexamethasone (DEX) on PEM sensitivity in vitro and in xenograft models. DEX co-administration reduced chemotherapy sensitivity to PEM in xenograft models. DEX co-administration promoted cell growth and weakened senescence growth arrest, such as altered secretions of proinflammatory and mitogenic cytokines, reminiscent of a senescence associate secretory phenotype (SASP). CSCs in DEX co-administration group were subsequently found to be less sensitive towards PEM treatment as measured by cell proliferation and generation of tumor spheres in the presence of PEM. Survival molecule B-cell lymphoma-2 (Bcl-2) may involve in this process and blockage of Bcl-2 could reverse altered senescence and CSCs abilities, thus alleviated PEM insensitivity. As such, DEX might suppress the antitumor activity of PEM through altered SASP level that had induced traits similar to CSCs.

Copyright © 2018 Elsevier Ltd. All rights reserved.

In plain English

This laboratory study tested whether dexamethasone (DEX), a steroid often given alongside the chemotherapy drug pemetrexed (PEM), changes how well PEM works against non-small cell lung cancer (NSCLC). It did not study asbestos, patients, or mesothelioma cells. The authors grew human NSCLC tumors (H1650 and A549 cells) in male nude mice and treated them with PEM with or without DEX. In mice, tumors grew more with PEM plus DEX than with PEM alone, and DEX shortened the longer median survival seen with PEM. In four non-squamous NSCLC cell lines, DEX reversed PEM's growth-inhibiting effect; PEM itself inhibited growth less in a squamous line. DEX reduced signs of PEM-induced senescence, a permanent stop in cell growth. It also suppressed PEM's increase in IL-6, IL-8, IL-1β and MCP-1, and increased cells carrying cancer stem cell markers. With DEX, cells formed 37 plus or minus 3 spheroids per 5×10³, compared with 6 plus or minus 1 with PEM alone. DEX raised the survival protein Bcl-2. The authors concluded that DEX co-administration induces PEM insensitivity and that giving the two together needs careful consideration.

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 using human lung cancer cell lines in vitro and tumor xenografts in mice (animal experiment)
• Who was studied: Human NSCLC cell lines (NCI-H1650, A549, NCI-H2228, NCI-H292 and NCI-H226) bought in Shanghai, China, plus human bronchial epithelial cells (BEAS-2B). H1650 and A549 cells were also grown as tumors in 4-week-old male nude mice. The number of mice is not stated.
• Exposure: Drug treatments, not asbestos. Mice received pemetrexed 100 mg/kg (or saline vehicle) by injection once a week for 4 weeks, with or without dexamethasone 0.2 mg/kg by gavage twice daily around each PEM dose. Cells received PEM 0.3 µM with or without DEX 1 µM.
• Main results:
  • In mice with H1650 or A549 tumors, PEM plus DEX resulted in more tumor growth than PEM alone (no numbers given in the text).
  • PEM-treated mice survived significantly longer than vehicle-treated mice. Adding DEX shortened this prolonged median survival (no survival times given in the text).
  • In four non-squamous NSCLC cell lines (H1650, A549, H2228, H292), DEX reversed PEM's inhibition of colony formation and cell proliferation.
  • PEM had less growth-inhibiting effect in the squamous cell line H226 and in human bronchial epithelial cells (BEAS-2B).
  • PEM increased activity of the senescence marker SA-β-gal, and DEX co-treatment decreased it, in H1650, A549, H2228 and H292 cells.
  • PEM increased the secreted factors IL-6, IL-8, IL-1β and MCP-1, and DEX suppressed these increases (antibody arrays, ELISA and real-time PCR).
  • Cells co-treated with DEX had more cells carrying the cancer stem cell markers CD44 and CD133 than cells treated with PEM alone.
  • At day 14, sphere formation was 37 plus or minus 3 spheroids per 5×10³ cells in the DEX co-medication group, compared with 6 plus or minus 1 per 5×10³ in the PEM-treated group.
  • DEX co-medication increased the survival protein Bcl-2 but not Bcl-xl or Mcl-1. The pro-apoptotic protein Bax was decreased.
  • Blocking Bcl-2 increased SA-β-gal activity compared with DEX co-medication plus control siRNA or DMSO.
• The authors' conclusion: The authors concluded that, in vitro and in vivo, DEX co-administration induces PEM insensitivity through reduced senescence and altered SASPs, and that combined use of DEX with PEM in lung carcinoma needs careful consideration.
• Limitations the authors state:
  • The authors note the effect may not apply to all drugs or all cancers, and that further studies with different cell types and anticancer drugs are needed.

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Lung Cancer, Antifolate, Non-Small Cell Lung Cancer, Pleural Mesothelioma, Chemotherapy, Cytokine.

Related studies

• Single-dose dexamethasone for the prevention of pemetrexed associated cutaneous adverse reactions — R. Elsoueidi, M.J. Lander, et al. (2016)
• Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage — G. Rombolà, F. Vaira, et al. (2015)
• Pemetrexed-induced scleroderma-like conditions in the lower legs of a patient with non-small cell lung carcinoma — K. Ishikawa, T. Sakai, et al. (2016)
• Safety of Same-Day Vitamin B12 Supplementation in Patients Receiving Pemetrexed for the Treatment of Non-Small-Cell Lung Cancer or Pleural Mesothelioma: A Retrospective Analysis — Z. Schlei, W. Tan, et al. (2018)
• Pemetrexed-Induced Rash May Be Prevented by Supplementary Corticosteroids — T. Sakurada, S. Kakiuchi, et al. (2015)
• Pharmacokinetics of aprepitant and dexamethasone after administration of chemotherapeutic agents and effects of plasma substance P concentration on chemotherapy-induced nausea and vomiting in Japanese cancer patients — T. Takahashi, Y. Nakamura, et al. (2011)

Browse more research in Food and Chemical Toxicology, or return to medical research.