Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs

Oncotarget
Jennifer M FoxXiaochun Chen

Abstract

Artemisinins, endoperoxide-containing molecules, best known as antimalarials, have potent antineoplastic activity. The established antimalarial, artesunate (AS), and the novel artemisinin-derived trioxane diphenylphosphate dimer 838 (ART-838) inhibited growth of all 23 tested acute leukemia cell lines, reduced cell proliferation and clonogenicity, induced apoptosis, and increased intracellular levels of reactive oxygen species (ROS). ART-838 was 88-fold more potent that AS in vitro, inhibiting all leukemia cell lines at submicromolar concentrations. Both ART-838 and AS cooperated with several established antileukemic drugs and newer kinase inhibitors to inhibit leukemia cell growth. ART-838 had a longer plasma half-life than AS in immunodeficient NOD-SCID-IL2Rgnull (NSG) mice, remaining at effective antileukemic concentrations for >8h. Intermittent cycles of ART-838 inhibited growth of acute leukemia xenografts and primagrafts in NSG mice, at higher potency than AS. Based on these preclinical data, we propose that AS, with its established low toxicity and low cost, and ART-838, with its higher potency and longer persistence in vivo, should be further developed toward integration into antileukemic regimens.

References

Jun 1, 1993·Journal of Natural Products·H J WoerdenbagA W Konings
Oct 19, 2000·The American Journal of Tropical Medicine and Hygiene·A NontprasertN J White
Mar 7, 2003·Journal of Medicinal Chemistry·Gary H PosnerTheresa A Shapiro
Dec 31, 2003·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Helene JouinDaniel Dive
Sep 1, 2004·Free Radical Biology & Medicine·Thomas EfferthManfred Marschall
Dec 22, 2006·Journal of Medicinal Chemistry·Adebusola A AlagbalaBarbara A Foster
Aug 30, 2008·Trends in Pharmacological Sciences·Sanjeev KrishnaHenry M Staines
Sep 4, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Junmei HouHui Wang
Nov 8, 2008·The Journal of Antimicrobial Chemotherapy·John G D'AngeloLorraine Jones-Brando
Jun 18, 2009·International Journal of Cancer. Journal International Du Cancer·Luke H StockwinMaja A Bumke
Aug 25, 2009·Biochemical Pharmacology·Martin MichaelisJindrich Cinatl
Dec 17, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ann W GramzaMichael C Heinrich
Feb 10, 2010·Expert Opinion on Investigational Drugs·Munira Shabbir, Robert Stuart
Feb 18, 2010·Critical Reviews in Toxicology·Thomas Efferth, Bernd Kaina
Nov 13, 2010·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Delia BethellMark M Fukuda
Jan 18, 2011·Expert Opinion on Investigational Drugs·Rina Barouch-Bentov, Karsten Sauer
Sep 13, 2011·Cell·Louis H Miller, Xinzhuan Su
Dec 17, 2011·Journal of Biomedicine & Biotechnology·Maria P Crespo-Ortiz, Ming Q Wei
Nov 1, 2002·Current Protocols in Pharmacology·Melinda Hollingshead
Apr 25, 2013·International Journal of Hematology·Michael R Grunwald, Mark J Levis
Nov 30, 2013·Nature Reviews. Drug Discovery·Chiara GorriniTak W Mak
Dec 10, 2013·Pharmacology & Therapeutics·Wanxing Eugene HoW S Fred Wong

❮ Previous
Next ❯

Citations

Feb 21, 2018·Journal of Hematology & Oncology·Thea Kristin VåtsveenMorten P Oksvold
Jun 24, 2017·Medicinal Research Reviews·Yin Kwan WongJigang Wang
Feb 18, 2017·Cancer Chemotherapy and Pharmacology·Archana Bhaw-Luximon, Dhanjay Jhurry
Apr 11, 2018·Natural Products and Bioprospecting·Yunqin ZhangZhili Zuo
Dec 13, 2018·Anti-cancer Drugs·Nelson Siukei LamJames C G Doery
Nov 4, 2020·Cancer Chemotherapy and Pharmacology·R I MancusoS T Olalla Saad
Jun 3, 2020·Seminars in Cancer Biology·Xiaohua Lu, Thomas Efferth
May 15, 2021·Infectious Agents and Cancer·Toby EllisBahijja Tolulope Raimi-Abraham

❮ Previous
Next ❯

Methods Mentioned

BETA
xenografts
flow cytometry
Fluorescence
xenograft

Software Mentioned

FlowJo
CompuSyn
Prism

Related Concepts

Related Feeds

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease with approximately 20,000 cases per year in the United States. AML also accounts for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. Here is the latest research on this disease.

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

AML: Role of LSD1 by CRISPR (Keystone)

Find the latest rersearrch on the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML) here.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis