Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress

Wang, Jiaqiao; Yan, Xu; Wan, Huihui; Hu, June

doi:10.1016/j.bbrc.2018.02.063

Cited by 52 publications

(52 citation statements)

References 25 publications

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“…23 Studies have shown that Z-VAD-FMK, a pan-caspase inhibitor, eliminates the pro-apoptotic influence of ivermectin on K562, U87, NBM CD34, CML and T98G cells, which indicates that ivermectin induces apoptosis in glioblastoma and chronic myeloid leukaemia cells through a caspasedependent pathway. 24,25 OCI-AML2 leukaemia cells treated with ivermectin exhibit the same results. 11 KPNB1, which encodes a nuclear transport factor, is a new therapeutic target gene.…”

Section: Ivermectin Induces Caspase-dependent Apoptosissupporting

confidence: 52%

<p>Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin</p>

Liu

Zhang

Cheng

et al. 2020

DDDT

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Ivermectin, a dihydro derivative of avermectin (AVM), was introduced into the veterinary, agricultural and aquaculture markets for animal health in 1981. Ivermectin was soon adopted in 1987 as a human medicine that was originally used for the treatment of onchocerciasis, a parasitic infection. Since then, ivermectin has also been used to control other human diseases and has exerted a significant effect on human health and welfare. In the past decade, many published studies have attempted to determine the role of ivermectin in cancer. In this review, we summarize the published studies to define the current progress in the characterization of ivermectin. Ivermectin causes cell death in cancer cell lines by inducing PAK1-mediated cytostatic autophagy, caspase-dependent apoptosis and immunogenic cell death (ICD) through the modulation of some pathways, including the WNT-T cell factor (TCF), Hippo and Akt/ mTOR pathways. Ivermectin can affect the growth and proliferation of cancer cells and plays several different roles, such as its functions as an RNA helicase, a small-molecule mimetic of the surface-induced dissociation (SID) peptide, an activator of chloride channel receptors, and an inducer of mitochondrial dysfunction and oxidative stress. In addition, ivermectin induces the multidrug resistance protein (MDR), has potent anti-mitotic activity, targets angiogenesis and inhibits cancer stem-like cells (CSCs). Many studies have proven that ivermectin exerts antitumour effects and might thus benefit patients with cancer after sufficient clinical trials.

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Section: Ivermectin Induces Caspase-dependent Apoptosissupporting

confidence: 52%

<p>Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin</p>

Liu

Zhang

Cheng

et al. 2020

DDDT

View full text Add to dashboard Cite

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“…(ie, expressing a cell surface marker indicating stemness) and found that ivermectin induced caspase-dependent apoptosis in CML but not normal hematopoietc cells via mitochondrial dysfunction and oxidative stress. 44 Molecular signaling propagated by kinases in the AKT/mTOR pathway was reduced following ivermectin treatment, and increases in levels of superoxide and total intracellular ROS were both observed. Additionally, ivermectin was found to synergize with TKIs nilotinib and dasatinib to increase the amount of CML apoptosis.…”

Section: Figurementioning

confidence: 99%

“…Ivermectin induces autophagy in breast cancer tumors by interfering with the mTOR/Akt pathway, and has been shown to induce cell death in AML cells via chloride‐dependent membrane hyperpolarization and increased ROS . This study compared CML cell line K562 to primary CML cells and normal bone marrow cells, the latter two both CD‐34+ (ie, expressing a cell surface marker indicating stemness) and found that ivermectin induced caspase‐dependent apoptosis in CML but not normal hematopoietc cells via mitochondrial dysfunction and oxidative stress . Molecular signaling propagated by kinases in the AKT/mTOR pathway was reduced following ivermectin treatment, and increases in levels of superoxide and total intracellular ROS were both observed.…”

Section: Chronic Myeloid Leukemiamentioning

confidence: 99%

“…Molecular signaling propagated by kinases in the AKT/mTOR pathway was reduced following ivermectin treatment, and increases in levels of superoxide and total intracellular ROS were both observed. Additionally, ivermectin was found to synergize with TKIs nilotinib and dasatinib to increase the amount of CML apoptosis . TKIs efficiently target differentiated cells, allowing leukemic stem cells to persist, thus further motivating the development of innovative treatment approaches for CML.…”

Section: Chronic Myeloid Leukemiamentioning

confidence: 99%

“…Additionally, ivermectin was found to synergize with TKIs nilotinib and dasatinib to increase the amount of CML apoptosis. 44 gov, Table 1). While great strides have been made during the last half century to treat AML thus improving survival rates, it remains an aggressive malignancy with poor prognoses of less than 30% 5-year relative survival rates for all patients (seer.cancer.gov).…”

Section: Figurementioning

confidence: 99%

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Metabolic underpinnings of leukemia pathology and treatment

2018

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Background Carcinogenic transformation of white blood cells during hematopoiesis leads to the development of leukemia, a cancer characterized by incompetent immune cells and a disruption of normal bone marrow function. Leukemias are diverse in type, affected population, prognosis, and treatment regimen, yet a common theme in leukemia is the dysregulated metabolism of leukemic cells and leukemic stem cells with respect to their noncancerous counterparts. Recent findings In this review, we highlight current findings that elucidate metabolic traits unique to the four major types of leukemia, which confer carcinogenic survival but can be potentially exploited for therapeutic intervention. These metabolic features can work in conjunction with or be independent of unique aspects of the bone marrow microenvironment that can also influence cell survival and proliferation, thus sustaining carcinogenesis. Conclusion Deepening our understanding of the interactions of leukemias with their niche environments in vivo will inform future treatments for leukemia, particularly for those that are refractive to tyrosine kinase inhibitors and other therapeutic mainstays.

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Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy

Newell,

van der Watt,

Leaner

2023

IUBMB Life

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Systemic modalities are crucial in the management of disseminated malignancies and liquid tumours. However, patient responses and tolerability to treatment are generally poor and those that enter remission often return with refractory disease. Combination therapies provide a methodology to overcome chemoresistance mechanisms and address dose‐limiting toxicities. A deeper understanding of tumorigenic processes at the molecular level has brought a targeted therapy approach to the forefront of cancer research, and novel cancer biomarkers are being identified at a rapid rate, with some showing potential therapeutic benefits. The Karyopherin superfamily of proteins is soluble receptors that mediate nucleocytoplasmic shuttling of proteins and RNAs, and recently, nuclear transport receptors have been recognized as novel anticancer targets. Inhibitors against nuclear export have been approved for clinical use against certain cancer types, whereas inhibitors against nuclear import are in preclinical stages of investigation. Mechanistically, targeting nucleocytoplasmic shuttling has shown to abrogate oncogenic signalling and restore tumour suppressor functions through nuclear sequestration of relevant proteins and mRNAs. Hence, nuclear transport inhibitors display broad spectrum anticancer activity and harbour potential to engage in synergistic interactions with a wide array of cytotoxic agents and other targeted agents. This review is focussed on the most researched nuclear transport receptors in the context of cancer, XPO1 and KPNB1, and highlights how inhibitors targeting these receptors can enhance the therapeutic efficacy of standard of care therapies and novel targeted agents in a combination therapy approach. Furthermore, an updated review on the therapeutic targeting of lesser characterized karyopherin proteins is provided and resistance to clinically approved nuclear export inhibitors is discussed.

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Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress

Cited by 52 publications

References 25 publications

<p>Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin</p>

<p>Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin</p>

Metabolic underpinnings of leukemia pathology and treatment

Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy

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