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Artemisinin-type drugs for the treatment of hematological malignancies

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Abstract

Qinghaosu, known as artemisinin (ARS), has been for over two millennia, one of the most common herbs prescribed in traditional Chinese medicine (TCM). ARS was developed as an antimalarial drug and currently belongs to the established standard treatments of malaria as a combination therapy worldwide. In addition to the antimalarial bioactivity of ARS, anticancer activities have been shown both in vitro and in vivo. Like other natural products, ARS acts in a multi-specific manner also against hematological malignancies. The chemical structure of ARS is a sesquiterpene lactone, which contains an endoperoxide bridge essential for activity. The main mechanism of action of ARS and its derivatives (artesunate, dihydroartemisinin, artemether) toward leukemia, multiple myeloma, and lymphoma cells comprises oxidative stress response, inhibition of proliferation, induction of various types of cell death as apoptosis, autophagy, ferroptosis, inhibition of angiogenesis, and signal transducers, as NF-κB, MYC, amongst others. Therefore, new pharmaceutically active compounds, dimers, trimers, and hybrid molecules, could enhance the existing therapeutic alternatives in combating hematologic malignancies. Owing to the high potency and good tolerance without side effects of ARS-type drugs, combination therapies with standard chemotherapies could be applied in the future after further clinical trials in hematological malignancies.

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Abbreviations

AML:

Acute myeloid leukemia

AMoL:

Acute monocytic leukemia

AMPK:

AMP-activated protein kinase

AP-1:

Activator protein-1

Ara-C:

Cytarabine

ARM:

Artemether

ARS:

Artemisinin

ART:

Artesunate

ATO:

Arsenic trioxide

B-ALL:

B-acute lymphoblastic leukemia

BM:

Bone marrow

CML:

Chronic myeloid leukemia

CuZnSOD:

Copper, zinc-superoxide dismutase

DA:

Decitabine

DHA:

Dihydroartemisinin

DLBCL:

Diffuse large B-cell lymphoma

DM:

Dexamethasone

DX:

Deferoxamine

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinase

GEM:

Genetically-engineered mouse

GpA:

Glycophorin A receptor

GPX1/2:

Glutathione peroxidases 1 and 2

HBO2 :

Hyperbaric oxygen

HET:

Dihydroethidine

H2O2 :

Hydrogen peroxide

IFN-α:

Interferon-α

JNK:

C-Jun-N-terminal kinase

MAPK:

Mitogen-activated protein kinases

MM:

Multiple myeloma

MMP:

Mitochondrial membrane potential

MnSOD:

Manganese-superoxide dismutase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

O2 − :

Superoxide

PBMC:

Peripheral blood mononuclear cells

PBN:

N-Tert-butyl-alpha-phenylnitrone

P-gp:

P-Glycoprotein

PPP:

Pentose phosphate pathway

ROS:

Reactive oxygen species

SS:

Sodium salicylate

STAT3:

Signal transducer and activator of transcription-3

TCM:

Traditional Chinese medicine

TfR:

Transferrin receptor

VEGF:

Vascular endothelial growth factor

WHO:

World Health Organization

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Acknowledgements

The authors would like to thank São Paulo Research Foundation (FAPESP) and Ministry of Science, Technology, Innovations and Communications (CNPq) for financial support and Raquel S. Foglio for the writing assistance and English revision.

Funding

This study was funded by grant # 2017/21801-2 (STOS), 2014/16008-3 (MAF), 2016/18384-8 (MAF), São Paulo Research Foundation (FAPESP) and Ministry of Science, Technology, Innovations and Communications (CNPq) grant # 301676/2013-5 (STOS) CNPq #142286/2017 (RIM) and 401904/2012-1 (MAF).

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Authors and Affiliations

  1. Hematology and Hemotherapy Center, University of Campinas, HEMOCENTRO UNICAMP, Campinas, São Paulo, Brazil

    R. I. Mancuso & S. T. Olalla Saad

  2. Faculty of Pharmaceutical Science, University of Campinas-UNICAMP, Campinas, São Paulo, Brazil

    M. A. Foglio

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  1. R. I. Mancuso
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  2. M. A. Foglio
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  3. S. T. Olalla Saad
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Design of the Review: RIM and STOS; Bibliographical review: RIM, STOS, MAF; Manuscript preparation: all authors. All authors reviewed and approved the final manuscript.

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Correspondence to S. T. Olalla Saad.

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Mancuso, R.I., Foglio, M.A. & Olalla Saad, S.T. Artemisinin-type drugs for the treatment of hematological malignancies. Cancer Chemother Pharmacol 87, 1–22 (2021). https://doi.org/10.1007/s00280-020-04170-5

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