Plumbagin induces apoptosis in lymphoma cells via oxidative stress mediated glutathionylation and inhibition of mitogen-activated protein kinase phosphatases (MKP1/2)

Checker, Rahul; Gambhir, Lokesh; Sharma, Deepak; Kumar, Mukesh; Sandur, Santosh K.

doi:10.1016/j.canlet.2014.11.031

Cited by 50 publications

(25 citation statements)

References 68 publications

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“…Recently PLB was found to be a promising anticancer compound [10, 25]. Some previous studies have shown that PLB can induce oxidative stress in various cell lines, and induction of ROS production is involved in the biological functions of PLB [14, 26, 27]. In accordance with previous studies, results of the present study indicated that PLB induced a rapid increase in ROS production in DU145 and PC-3 cells.…”

Section: Discussionsupporting

confidence: 82%

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Plumbagin Triggers ER Stress-Mediated Apoptosis in Prostate Cancer Cells via Induction of ROS

Huang

Xie

Pan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Prostate cancer (PCa) is the second most frequently diagnosed cancer in men worldwide. Currently available therapies for hormone-refractory PCa are only marginally effective. Plumbagin (PLB), a natural naphthoquinone isolated from the traditional folk medicine Plumbago zeylanica, is known to selectively kill tumor cells. Nevertheless, antitumor mechanisms initiated by PLB in cancer cells have not been fully defined. Methods: MTT assay was used to evaluate the effect of PLB on the viability of cancer cells. Cell apoptosis and reactive oxygen species (ROS) production were determined by flow cytometry. Protein expression was detected by western blotting. In vivo anti-tumor effect was measured by using tumor xenoqraft model in nude mice. Results: In the present study, we found that PLB decreases cancer cell growth and induces apoptosis in DU145 and PC-3 cells. In addition, by increasing intracellular ROS levels, PLB induced a lethal endoplasmic reticulum stress response in PCa cells. Importantly, blockage of ROS production significantly reversed PLB-induced ER stress activation and cell apoptosis. In vivo, we found that PLB inhibits the growth of PCa xenografts without exhibiting toxicity Treatment of mice bearing human PCa xenografts with PLB was also associated with induction of ER stress activation. Conclusion: Inducing ER stress by PLB thus discloses a previously unrecognized mechanism underlying the biological activity of PLB and provides an in-depth insight into the action of PLB in the treatment of hormone-refractory PCa.

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Section: Discussionsupporting

confidence: 82%

“…ROS generation has been reported to play an important role in the pro-apoptotic effects of PLB in some tumor cell lines [14, 15]. Therefore, we examined the levels of intracellular ROS in PLB-treated and untreated cells by flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

Plumbagin Triggers ER Stress-Mediated Apoptosis in Prostate Cancer Cells via Induction of ROS

Huang

Xie

Pan

et al. 2018

Cell Physiol Biochem

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“…Cells were permeabilised with PBS containing 0.1% Tween 20 for 3 min and 0.05% TritonX100 for 2 min at room temperature, and staining was performed using isotype control or pPI3K or pAKT or pGSK3β antibodies as described earlier (Checker, Gambhir, Sharma, Kumar, & Sandur, 2015). Vehicle treated cells served as control.…”

Section: Surface and Intracellular Antibody Stainingmentioning

confidence: 99%

Sulforaphane, a naturally occurring isothiocyanate, exhibits anti-inflammatory effects by targeting GSK3β/Nrf-2 and NF-κB pathways in T cells

Checker

Gambhir

Thoh

et al. 2015

Journal of Functional Foods

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A B S T R A C TA potent Nrf-2 activator sulforaphane (SF), which is currently under clinical trials for cancer therapy, was employed to elucidate the role of Keap1/Nrf-2/ARE signalling pathway in T-cell responses. SF suppressed mitogen induced T-cell and B-cell proliferation. It also inhibited mitogen induced upregulation of T-cell (CD25 and CD69) and B-cell (CD80 and CD86) activation markers and suppressed secretion of cytokines (IL-2, IL-4, IL-6 and IFN-γ). SF induced oxidative stress and its anti-inflammatory effects were abrogated by thiol antioxidants. SF activated PI3K/AKT, leading to phosphorylation mediated suppression of GSK3β resulting in Nrf-2 activation. We also show for the first time that SF can prevent direct interaction between NF-κB and its consensus sequence by modulating thiol groups. It also suppressed homeostatic proliferation of T-cells and suppressed lipopolysaccharide induced proinflammatory mediators in macrophages. Our study shows that the potent anti-inflammatory effects of SF are mediated via modulation of PI3K/AKT/GSK3β/Nrf-2 and NF-κB pathway in T-cells.

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“…At higher doses, plumbagin ( >30 μmol/L) induces cell cycle arrest and apoptosis in some cancer cells (11,12). In contrast, low-dose plumbagin ( <5 μmol/L) cannot induce cell death, but exhibits antiinflammatory activity in macrophages and T cells (13)(14)(15).…”

Section: Oxidative Phosphorylation and Glycolysis Assaymentioning

confidence: 99%

Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2

Zhang

Deng

Kang

et al. 2016

Mol Med

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Sepsis is characterized by dysregulated systemic inflammation with release of early (for example, interleukin (IL)-1β) and late (for example, HMGB1) proinflammatory mediators from macrophages. Plumbagin, a medicinal plant-derived naphthoquinone, has been reported to exhibit antiinflammatory activity, but the underling mechanisms remain unclear. Here, we have demonstrated that plumbagin inhibits the inflammatory response through interfering with the immunometabolism pathway in activated macrophages. Remarkably, plumbagin inhibited lipopolysaccharide (LPS)-induced aerobic glycolysis by downregulating the expression of pyruvate kinase M2 (PKM2), a protein kinase responsible for the final and rate-limiting reaction step of the glycolytic pathway. Moreover, the NADPH oxidase 4 (NOX4)-mediated oxidative stress was required for LPS-induced PKM2 expression, because pharmacologic or genetic inhibition of NOX4 by plumbagin or RNA interference limited LPS-induced PKM2 expression, lactate production and subsequent proinflammatory cytokine (IL-1β and HMGB1) release in macrophages. Finally, plumbagin protected mice from lethal endotoxemia and polymicrobial sepsis induced by cecal ligation and puncture. These findings identify a new approach for inhibiting the NOX4/PKM2-dependent immunometabolism pathway in the treatment of sepsis and inflammatory diseases.

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Plumbagin induces apoptosis in lymphoma cells via oxidative stress mediated glutathionylation and inhibition of mitogen-activated protein kinase phosphatases (MKP1/2)

Cited by 50 publications

References 68 publications

Plumbagin Triggers ER Stress-Mediated Apoptosis in Prostate Cancer Cells via Induction of ROS

Plumbagin Triggers ER Stress-Mediated Apoptosis in Prostate Cancer Cells via Induction of ROS

Sulforaphane, a naturally occurring isothiocyanate, exhibits anti-inflammatory effects by targeting GSK3β/Nrf-2 and NF-κB pathways in T cells

Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2

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