Paclitaxel Impedes EGFR-mutated PC9 Cell Growth via Reactive Oxygen Species-mediated DNA Damage and EGFR/PI3K/AKT/mTOR Signaling Pathway Suppression

8-gingerol (8-Gin) is the series of phenolic substance that is extracted from ginger. Although many studies have revealed that 8-Gin has multiple pharmacological properties, the possible underlying mechanisms of 8-Gin against myocardial fibrosis (MF) remains unclear. The study examined the exact role and potential mechanisms of 8-Gin against isoproterenol (ISO)-induced MF. Male mice were intraperitoneally injected with 8-Gin (10 and 20 mg/kg/d) and concurrently subcutaneously injected with ISO (10 mg/kg/d) for 2 weeks. Electrocardiography, pathological heart morphology, myocardial enzymes, reactive oxygen species (ROS) generation, degree of apoptosis, and autophagy pathway-related proteins were measured. Our study observed 8-Gin significantly reduced J-point elevation and heart rate. Besides, 8-Gin caused a marked decrease in cardiac weight index and left ventricle weight index, serum levels of creatine kinase and lactate dehydrogenase (CK and LDH, respectively), ROS generation, and attenuated ISO-induced pathological heart damage. Moreover, treatment with 8-Gin resulted in a marked decrease in the levels of collagen types I and III and TGF-β in the heart tissue. Our results showed 8-Gin exposure significantly suppressed ISO-induced autophagosome formation. 8-Gin also could lead to down-regulation of the activities of matrix metalloproteinases-9 (MMP-9), Caspase-9, and Bax protein, up-regulation of the activity of Bcl-2 protein, and alleviation of cardiomyocyte apoptosis. Furthermore, 8-Gin produced an obvious increase in the expressions of the PI3K/Akt/mTOR signaling pathway-related proteins. Our data showed that 8-Gin exerted cardioprotective effects on ISO-induced MF, which possibly occurred in connection with inhibition of ROS generation, apoptosis, and autophagy via modulation of the PI3K/Akt/mTOR signaling pathway.

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Reactive Oxygen Species regulates cell growth via distinct signaling pathway independent of TOR

Mechanisms of Development ◽

10.1016/j.mod.2017.04.581 ◽

2017 ◽

Vol 145 ◽

pp. S19-S20

Author(s):

Ashish Toshniwal ◽

Sakshi Gupta ◽

Lolitika Mandal ◽

Sudip Mandal

Keyword(s):

Reactive Oxygen Species ◽

Cell Growth ◽

Signaling Pathway ◽

Reactive Oxygen ◽

Oxygen Species ◽

Distinct Signaling Pathway

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Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth

International Journal of Molecular Sciences ◽

10.3390/ijms22042088 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2088

Author(s):

Rosalin Mishra ◽

Long Yuan ◽

Hima Patel ◽

Aniruddha S. Karve ◽

Haizhou Zhu ◽

...

Keyword(s):

Breast Cancer ◽

Reactive Oxygen Species ◽

Dna Damage ◽

Cell Growth ◽

Cancer Cell ◽

Dna Damage Response ◽

Reactive Oxygen ◽

Oxygen Species ◽

Cancer Cell Growth ◽

Damage Response

RIDR-PI-103 is a novel reactive oxygen species (ROS)-induced drug release prodrug with a self-cyclizing moiety linked to a pan-PI3K inhibitor (PI-103). Under high ROS, PI-103 is released in a controlled manner to inhibit PI3K. The efficacy and bioavailability of RIDR-PI-103 in breast cancer remains unexplored. Cell viability of RIDR-PI-103 was assessed on breast cancer cells (MDA-MB-231, MDA-MB-361 and MDA-MB-453), non-tumorigenic MCF10A and fibroblasts. Matrigel colony formation, cell proliferation and migration assays examined the migratory properties of breast cancers upon treatment with RIDR-PI-103 and doxorubicin. Western blots determined the effect of doxorubicin ± RIDR-PI-103 on AKT activation and DNA damage response. Pharmacokinetic (PK) studies using C57BL/6J mice determined systemic exposure (plasma concentrations and overall area under the curve) and T1/2 of RIDR-PI-103. MDA-MB-453, MDA-MB-231 and MDA-MB-361 cells were sensitive to RIDR-PI-103 vs. MCF10A and normal fibroblast. Combination of doxorubicin and RIDR-PI-103 suppressed cancer cell growth and proliferation. Doxorubicin with RIDR-PI-103 inhibited p-AktS473, upregulated p-CHK1/2 and p-P53. PK studies showed that ~200 ng/mL (0.43 µM) RIDR-PI-103 is achievable in mice plasma with an initial dose of 20 mg/kg and a 10 h T1/2. (4) The prodrug RIDR-PI-103 could be a potential therapeutic for treatment of breast cancer patients.

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Nanoparticles induce autophagy via mTOR pathway inhibition and reactive oxygen species generation

Nanomedicine ◽

10.2217/nnm-2019-0387 ◽

2020 ◽

Vol 15 (14) ◽

pp. 1419-1435

Author(s):

Lu Jia ◽

Shuang-Li Hao ◽

Wan-Xi Yang

Keyword(s):

Reactive Oxygen Species ◽

Physicochemical Properties ◽

Signaling Pathway ◽

Human Body ◽

Reactive Oxygen Species Generation ◽

Reactive Oxygen ◽

Mtor Pathway ◽

Oxygen Species ◽

Mtor Signaling Pathway ◽

Pathway Inhibition

Due to their unique physicochemical properties, nanoparticles (NPs) have been increasingly developed for use in various fields. However, there has been both growing negative concerns with toxicity and positive realization of opportunities in nanomedicine, coming from the growing understanding of the associations between NPs and the human body, particularly relating to their cellular autophagic effects. This review summarizes NP-induced autophagy via the modulation of the mTOR signaling pathway and other associated signals including AMPK and ERK and also demonstrates how reactive oxygen species generation greatly underlies the regulation processes. The perspectives in this review aim to contribute to NP design, particularly in consideration of nanotoxicity and the potential for the precise application of NPs in nanomedicine.

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