JS-K, a nitric oxide donor, induces autophagy as a complementary mechanism inhibiting ovarian cancer

Liu, Bin; Huang, Xiaojie; Li, Yi-Fang; Liao, Weiguo; Li, Mingyi; Liu, Yi; He, Rong‐Rong; Feng, Du; Zhu, Runzhi; Kojima, Hiroshi

doi:10.1186/s12885-019-5619-z

Cited by 24 publications

(18 citation statements)

References 30 publications

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“…Recent approaches have focused on controlling the release and delivery of nitric oxide to inhibit cancer cell growth, such as with the use of nanoparticles [161,162,163,164,165]. These approaches have shown promising success, with NO improving platinum cancer therapy [163,166], enhancing cytotoxicity for synergistic treatments, achieving multidrug resistance reversal in mice models [164], and improving chemotherapy and preventing side effects of traditional chemotherapy [167].…”

Section: No Induction and No Donors In Cancer Therapymentioning

confidence: 99%

Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

Hays

Bonavida

2019

Antioxidants

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In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the transcription factor Yin-Yang 1 (YY1) and the programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on tumor cells to the PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the tumor cells to both cell killing and inhibition of tumor progression. Treatment with nitric oxide (NO) donors has been shown to sensitize many types of tumors to chemotherapy, immunotherapy, and radiotherapy. Treatment of cancer cell lines with NO donors has resulted in the inhibition of cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-tumor cytotoxic effector cells or other conventional therapies will result in a synergistic anticancer activity and tumor regression.

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Section: No Induction and No Donors In Cancer Therapymentioning

confidence: 99%

Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

Hays

Bonavida

2019

Antioxidants

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“…One hundred cells per experiment over 50 fields of view were quantified using ImageJ/FIJI. Briefly, individual cells were selected by using the selection tools and the mean fluorescent intensity per cell was obtained by the measure tool as previously described ( 70 , 71 ).…”

Section: Methodsmentioning

confidence: 99%

ROP16-Mediated Activation of STAT6 Suppresses Host Cell Reactive Oxygen Species Production, Facilitating Type III Toxoplasma gondii Growth and Survival

Kochanowsky

Thomas

Koshy

2021

mBio

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Polymorphic effector proteins determine the susceptibility of Toxoplasma gondii strains to IFN-γ-mediated clearance mechanisms deployed by murine host cells. However, less is known about the influence of these polymorphic effector proteins on IFN-γ-independent clearance mechanisms. Here, we show that deletion of one such polymorphic effector protein, ROP16, from a type III background leads to a defect in parasite growth and survival in unstimulated human fibroblasts and murine macrophages. Rescue of these defects requires a ROP16 with a functional kinase domain and the ability to activate a specific family of host cell transcription factors (STAT3, 5a, and 6). The growth and survival defects correlate with an accumulation of host cell reactive oxygen species (ROS) and are prevented by treatment with an ROS inhibitor. Exogenous activation of STAT3 and 6 suppresses host cell ROS production during infection with ROP16-deficient parasites and depletion of STAT6, but not STAT3 or 5a, causes an accumulation of ROS in cells infected with wild-type parasites. Pharmacological inhibition of NOX2 and mitochondrially derived ROS also rescues growth and survival of ROP16-deficient parasites. Collectively, these findings reveal an IFN-γ-independent mechanism of parasite restriction in human cells that is subverted by injection of ROP16 by type III parasites. IMPORTANCE Toxoplasma gondii is an obligate intracellular parasite that infects up to one-third of the world’s population. Control of the parasite is largely accomplished by IFN-γ-dependent mechanisms that stimulate innate and adaptive immune responses. Parasite suppression of IFN-γ-stimulated responses has been linked to proteins that the parasite secretes into its host cell. These secreted proteins vary by T. gondii strain and determine strain-specific lethality in mice. How these strain-specific polymorphic effector proteins affect IFN-γ-independent parasite control mechanisms in human and murine cells is not well known. This study shows that one such secreted protein, ROP16, enables efficient parasite growth and survival by suppressing IFN-γ-independent production of ROS by human and mouse cells.

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“…Then, the cells were washed with phosphate buffer saline (PBS) twice for 5 mins each time, and postfixed in 1% OsO 4 twice for 1 hr each time. Following acetone dehydration and epoxy resin embedding, ultra‐thin sections (70 nm) were prepared (Liu et al, 2019). Finally, the sections were stained with saturated uranyl acetate solution and lead acetate, and the autophagosomes were observed under transmission electron microscope (TEM) (HT7800, HITACHI, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of fucoidan on breast cancer cells and potential enhancement of their sensitivity to chemotherapy by regulating autophagy

Zhang

Xue

Wang

et al. 2021

Phytotherapy Research

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Fucoidan is a marine‐origin sulfated polysaccharide that has gained attention for its anticancer activities. However, the inhibitory effect of fucoidan on breast cancers by regulating autophagy and its mechanism are not clear, and the chemotherapeutic sensitization of fucoidan is largely unknown. In the present study, the anticancer potential of fucoidan was revealed in MCF‐7 and MDA‐MB‐231 cells. Additionally, we also studied the chemotherapeutic sensitization of fucoidan by combining chemotherapeutic drugs doxorubicin (ADM) and cisplatin (DDP) with fucoidan on breast cancer cells. In the two kinds of human breast cancer cells, cell viability was determined by 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay. Apoptosis was examined with flow cytometry. Transfection assay was used to examine autophagy flow. Western blot was used to examine the expressions of related proteins. Results suggested that fucoidan could induce autophagy and might enhance the sensitivity of breast cancer cells to chemotherapeutic drugs. Mechanistically, fucoidan induced autophagy in breast cancer cells by down‐regulating m‐TOR/p70S6K/TFEB pathway. In conclusion, our research revealed that fucoidan could induce autophagy of breast cancer cells by mediating m‐TOR/p70S6K/TFEB pathway, thus inhibiting tumor development. Furthermore, fucoidan might enhance the sensitivity of breast cancer cells to ADM and DDP, and this enhancement was related to autophagy.

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JS-K, a nitric oxide donor, induces autophagy as a complementary mechanism inhibiting ovarian cancer

Cited by 24 publications

References 30 publications

Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

ROP16-Mediated Activation of STAT6 Suppresses Host Cell Reactive Oxygen Species Production, Facilitating Type III Toxoplasma gondii Growth and Survival

Inhibition of fucoidan on breast cancer cells and potential enhancement of their sensitivity to chemotherapy by regulating autophagy

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