Volume 168, August 2023, 156234Author links open overlay panelAbstract

For more than 40 years, the epipodophyllotoxin drug etoposide is prescribed to treat cancer. This semi-synthetic compound remains extensively used to treat advanced small-cell lung cancer and in various chemotherapy regimen for autologous stem cell transplantation, and other anticancer protocols. Etoposide is a potent topoisomerase II poison, causing double-stranded DNA breaks which lead to cell death if they are not repaired. It is also a genotoxic compound, responsible for severe side effects and secondary leukemia occasionally. Beyond its well-recognized function as an inducer of cancer cell death (a “killer on the road”), etoposide is also useful to treat immune-mediated inflammatory diseases associated with a cytokine storm syndrome. The drug is essential to the treatment of hemophagocytic lymphohistiocytosis (HLH) and the macrophage activation syndrome (MAS), in combination with a corticosteroid and other drugs. The use of etoposide to treat HLH, either familial or secondary to a viral or parasitic infection, or treatment-induced HLH and MAS is reviewed here. Etoposide dampens inflammation in HLH patients via an inhibition of the production of pro-inflammatory mediators, such as IL-6, IL-10, IL-18, IFN-γ and TNF-α, and reduction of the secretion of the alarmin HMGB1. The modulation of cytokines production by etoposide contributes to deactivate T cells and to dampen the immune stimulation associated to the cytokine storm. This review discussed the clinical benefits and mechanism of action of etoposide (a “rider on the storm”) in the context of immune-mediated inflammatory diseases, notably life-threatening HLH and MAS. The question arises as to whether the two faces of etoposide action can apply to other topoisomerase II inhibitors.

Section snippetsEtoposide as an anticancer drug

Etoposide is a prototypical semi-synthetic epipodophylotoxin derivative used for the treatment of cancers for more than 40 years. Both etoposide (VP-16) and its analogue teniposide (VM-26) (Fig. 1) derive from the precursor deoxypodophyllotoxin which is an aryltetralin lignan commonly isolated from the roots and rhizomes of the endangered medicinal plant Sinopodophyllum hexandrum (American May apple or mandrake, Berberidaceae), or from other Podophyllum plant species such as P. peltatum [1], [2]

Etoposide to manage the cytokine storm syndrome

Under physiological conditions, the immune system relies on a variety of effector cells to produce cytokines, such as interleukins (IL), interferons (IFN), and chemokines, necessary to regulate the fragile equilibrium between pro- and anti-inflammatory mediators. Under pathological conditions, this equilibrium can become strongly disturbed, leading to a massive release of cytokines responsible for systemic damages, multi-organ failure, and possibly death. A major immune dysregulation,

Immune-mediated mechanism of etoposide: Cytokinic regulation

ETO is essentially a genotoxic agent, inducing DNA double-stand breaks via inhibition of topoisomerase II. In addition to inducing direct DNA damages, ETO has been shown to affect the development of immune responses by modulating of expression of different cytokines and immune mediators. The molecular origin of this ETO effect is not well understood at present. The drug is capable of suppressing the expression and/or function of pro-inflammatory cytokines such as interleukins IL-1 and IL-6,

Discussion

ETO is an essential drug for cancer chemotherapy [94], [95]. It is also the mainstay of treatment for hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). This non-tumoral use of ETO is less known but equally important. The activity relies on the capacity of ETO to reduce production of pro-inflammatory signals, such as interleukins IL-6, IL-10 and IL-18, and the alarmin protein HMGB1, contributing to the deactivation of T cells. Here, ETO functions essentially as

Funding

This research received no external funding.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The OncoLille Institute has been supported by a grant from Contrat de Plan Etat-Région CPER Cancer 2015–2020.

References (105)H. Pan et al.Acute myeloid leukemia following etoposide therapy for EBV-associated hemophagocytic lymphohistiocytosis: a case report and a brief review of the literature

BMC Pediatr.

(2016)

J. Bouguila et al.Treatment of severe hemophagocytic syndrome associated with visceral leishmaniasis

Arch. Pediatr.

(2010)

M. Aliyu et al.Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach

Int. Immunopharmacol.

(2022)

K. Fousek et al.Interleukin-8: A chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression

Pharmacol. Ther.

(2021)

T. Chen et al.Leukemia-derived exosomes induced IL-8 production in bone marrow stromal cells to protect the leukemia cells against chemotherapy

Life Sci.

(2019)

J. Zhang et al.Topoisomerase 2 inhibitor etoposide promotes interleukin-10 production in LPS-induced macrophages via upregulating transcription factor Maf and activating PI3K/Akt pathway

Int. Immunopharmacol.

(2021)

A. De Matteis et al.Expansion of CD4dimCD8+ T cells characterizes macrophage activation syndrome and other secondary HLH

Blood

(2022)

Z. Shah et al.Podophyllotoxin: History, recent advances and future prospects

Biomolecules

(2021)

A. Patyra et al.Extraction Techniques and Analytical Methods for Isolation and Characterization of Lignans

Plants (Basel).

(2022)

B.J. Schultz et al.Total biosynthesis for milligram-scale production of etoposide intermediates in a plant chassis

J. Am. Chem. Soc.

(2019)

D. Decembrino et al.Synthesis of (-)-deoxypodophyllotoxin and (-)-epipodophyllotoxin via a multi-enzyme cascade in E. coli

Microb. Cell Fact.

(2021)

H. Li et al.Clinical impact of the etoposide injection shortage

J. Oncol. Pharm. Pract.

(2020)

A. Montecucco et al.Molecular mechanisms of etoposide

EXCLI J.

(2015)

Q. Liu et al.First-line chemo-immunotherapy for extensive-stage small-cell lung cancer: A United States-based cost-effectiveness analysis

Front. Oncol.

(2021)

L. Hahn et al.BeEAM conditioning regimen is a safe, efficacious and economical alternative to BEAM chemotherapy

Sci. Rep.

(2021)

H.Y. Fan et al.Insight into the molecular mechanism of podophyllotoxin derivatives as anticancer drugs

Front. Cell. Dev. Biol.

(2021)

X. Li et al.First-line treatment of camrelizumab combined with chemotherapy in advanced gastroenteropancreatic neuroendocrine carcinoma: Study protocol for a prospective, multicenter, phase II study

Front. Oncol.

(2022)

S. Hagiwara et al.Autologous peripheral blood stem cell transplantation for relapsed/refractory HIV-associated lymphoma: a phase II clinical study

Int. J. Hematol.

(2020)

J.P. Brooks et al.Etoposide phosphate for pediatric orthopedic malignancies after intravenous etoposide hypersensitivity

J. Oncol. Pharm. Pract.

(2020)

X. Ma et al.Formulation and physicochemical and biological characterization of etoposide-loaded submicron emulsions with biosurfactant of sophorolipids

AAPS PharmSciTech.

(2022)

B. Martin et al.Preparation of parenteral nanocrystal suspensions of etoposide from the excipient free dry state of the drug to enhance in vivo antitumoral properties

Sci. Rep.

(2020)

S.K. Jha et al.Enhanced oral bioavailability of an etoposide multiple nanoemulsion incorporating a deoxycholic acid derivative-lipid complex

Drug Deliv.

(2020)

A. Alsalhi et al.Self-assembled nanomicelles to enhance solubility and anticancer activity of etoposide

Assay Drug Dev. Technol.

(2021)

M.R. Sarwar et al.Availability of anticancer medicines in public and private sectors, and their affordability by low, middle and high-income class patients in Pakistan

BMC Cancer.

(2018)

Y. Pommier et al.Human topoisomerases and their roles in genome stability and organization

Nat. Rev. Mol. Cell. Biol.

(2022)

M. Atwal et al.Intercalating TOP2 poisons attenuate topoisomerase action at higher concentrations

Mol. Pharmacol.

(2019)

I.G. Cowell et al.Model for MLL translocations in therapy-related leukemia involving topoisomerase IIβ-mediated DNA strand breaks and gene proximity

Proc. Natl. Acad Sci. USA

(2012)

Q. Nian et al.T-cell protein tyrosine phosphatase is irreversibly inhibited by etoposide-quinone, a reactive metabolite of the chemotherapy drug etoposide

Mol. Pharmacol.

(2019)

N. Kajita et al.Double recurrence of double cancers: Rhabdomyosarcoma and secondary AML

Pediatr. Int.

(2020)

R.Q. Cron et al.Cytokine storm syndrome

Annu. Rev. Med.

(2023)

S. Kolachana et al.Haemophagocytic lymphocytic histiocytosis/macrophage activation syndrome with acute inflammatory gastroenteritis

BMJ Case Rep.

(2022)

P. Peterlin et al.Dramatic recovery after etoposide phosphate infusion for hemophagocytic lymphohistiocytosis/macrophage activation syndrome following treatment with tisagenlecleucel in a young patient with relapsed acute lymphoblastic leukemia: A case report

Acta. Haematol.

(2022)

S. Wang et al.Etoposide combined with ruxolitinib for refractory hemophagocytic lymphohistiocytosis during pregnancy: a case report and literature review

Hematology

(2019)

A. Masood et al.Efficacy and safety of allogeneic hematopoietic stem cell transplant in adults with hemophagocytic lymphohistiocytosis: A systematic review of literature

Bone Marrow Transplant.

(2022)

T.S. Ponnatt et al.Hemophagocytic Lymphohistiocytosis

Arch. Pathol. Lab. Med.

(2022)

X.J. Xu et al.Dilemmas in diagnosis and management of hemophagocytic lymphohistiocytosis in children

World J. Pediatr.

(2020)

A. Horne et al.Efficacy of moderately dosed etoposide in macrophage activation syndrome-hemophagocytic lymphohistiocytosis

J. Rheumatol.

(2021)

G.E. Janka et al.Clinical features, diagnosis and therapy of familial haemophagocytic lymphohistiocytosis

Acta Paediatr.

(2021)

H. Tsuboi et al.Activation mechanisms of monocytes/macrophages in adult-onset Still disease

Front. Immunol.

(2022)

R. Wang et al.Short-term, low-dose etoposide in refractory adult-onset Still's disease-associated macrophage activation syndrome

Clin. Rheumatol.

(2022)

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