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Santosh K Sandur - One of the best experts on this subject based on the ideXlab platform.
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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
Cancer Letters, 2015Co-Authors: Rahul Checker, Deepak Sharma, Lokesh Gambhir, Mukesh Kumar, Santosh K SandurAbstract:Maintaining cellular redox homeostasis is imperative for the survival and normal functioning of cells. This study describes the role and regulation of MAPKinases in oxidative stress mediated apoptosis. Plumbagin, a vitamin K3 analog and a pro-oxidant, was employed and it induced apoptosis in both mouse and human T-cell lymphoma cell lines via increased oxidative stress, caspase activity and loss of mitochondrial membrane potential. The pro-oxidant and cytotoxic effects of Plumbagin were sensitive to antioxidants indicating a decisive role of cellular redox balance. Plumbagin induced persistent activation of JNK and pharmacological inhibition as well as shRNA-mediated JNK knock-down rescued cells from Plumbagin-induced apoptosis. Further, Plumbagin induced cytochrome c release, FasL expression and Bax levels via activation of JNK pathway. Exposure of lymphoma cells to Plumbagin led to inhibition of total and specific phosphatase activity, increased total protein S-glutathionylation and induced glutathionylation of dual specific phosphatase- 1 and 4 (MKP-1 and MKP-2). The in vivo anti-tumor efficacy of Plumbagin was demonstrated using a mouse model. In conclusion, oxidative stress mediated tumor cytotoxicity operates through sustained JNK activation via a novel redox-mediated regulation of MKP-1 and MKP-2.
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Plumbagin a vitamin k3 analogue abrogates lipopolysaccharide induced oxidative stress inflammation and endotoxic shock via nf κb suppression
Inflammation, 2014Co-Authors: Rahul Checker, Raghavendra S Patwardhan, Deepak Sharma, Jisha Menon, Maikho Thoh, Santosh K Sandur, Krishna B Sainis, T B PoduvalAbstract:Plumbagin has been reported to modulate cellular redox status and suppress NF-κB. In the present study, we investigated the effect of Plumbagin on lipopolysaccharide (LPS)-induced endotoxic shock, oxidative stress and inflammatory parameters in vitro and in vivo. Plumbagin inhibited LPS-induced nitric oxide, TNF-α, IL-6 and prostaglandin-E2 production in a concentration-dependent manner in RAW 264.7 cells without inducing any cell death. Plumbagin modulated cellular redox status in RAW cells. Plumbagin treatment significantly reduced MAPkinase and NF-κB activation in macrophages. Plumbagin prevented mice from endotoxic shock-associated mortality and decreased serum levels of pro-inflammatory markers. Plumbagin administration ameliorated LPS-induced oxidative stress in peritoneal macrophages and splenocytes. Plumbagin also attenuated endotoxic shock-associated changes in liver and lung histopathology and decreased the activation of ERK and NF-κB in liver. These findings demonstrate the efficacy of Plumbagin in preventing LPS-induced endotoxemia and also provide mechanistic insights into the anti-inflammatory effects of Plumbagin.
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Plumbagin inhibits proliferative and inflammatory responses of t cells independent of ros generation but by modulating intracellular thiols
Journal of Cellular Biochemistry, 2010Co-Authors: Rahul Checker, Deepak Sharma, Santosh K Sandur, T B Poduval, Gosukonda Subrahmanyam, Sunil Krishnan, Krishna B SainisAbstract:Plumbagin inhibited activation, proliferation, cytokine production, and graft-versus-host disease in lymphocytes and inhibited growth of tumor cells by suppressing nuclear factor-kappaB (NF-kappaB). Plumbagin was also shown to induce reactive oxygen species (ROS) generation in tumor cells via an unknown mechanism. Present report describes a novel role of cellular redox in modulation of immune responses in normal lymphocytes by Plumbagin. Plumbagin depleted glutathione (GSH) levels that led to increase in ROS generation. The decrease in GSH levels was due to direct reaction of Plumbagin with GSH as evinced by mass spectrometric and HPLC analysis. Further, addition of Plumbagin to cells resulted in decrease in free thiol groups on proteins and increase in glutathionylation of proteins. The suppression of mitogen-induced T-cell proliferation and cytokine (IL-2/IL-4/IL-6/IFN-gamma) production by Plumbagin was abrogated by thiol antioxidants but not by non-thiol antioxidants confirming that thiols but not ROS play an important role in biological activity of Plumbagin. Plumbagin also abrogated mitogen-induced phosphorylation of ERK, IKK, and degradation of IkappaB-alpha. However, it did not affect phosphorylation of P38, JNK, and AKT. Our results for the first time show that antiproliferative effects of Plumbagin are mediated by modulation of cellular redox. These results provide a rationale for application of thiol-depleting agents as anti-inflammatory drugs.
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5 hydroxy 2 methyl 1 4 naphthoquinone a vitamin k3 analogue suppresses stat3 activation pathway through induction of protein tyrosine phosphatase shp 1 potential role in chemosensitization
Molecular Cancer Research, 2010Co-Authors: Santosh K Sandur, Manoj K Pandey, Bokyung Sung, Bharat B AggarwalAbstract:The activation of signal transducers and activators of transcription 3 (STAT3) has been linked with carcinogenesis through survival, proliferation, and angiogenesis of tumor cells. Agents that can suppress STAT3 activation have potential not only for prevention but also for treatment of cancer. In the present report, we investigated whether 5-hydroxy-2-methyl-1,4-naphthoquinone (Plumbagin), an analogue of vitamin K, and isolated from chitrak (Plumbago zeylanica), an Ayurvedic medicinal plant, can modulate the STAT3 pathway. We found that Plumbagin inhibited both constitutive and interleukin 6-inducible STAT3 phosphorylation in multiple myeloma (MM) cells and this correlated with the inhibition of c-Src, Janus-activated kinase (JAK)1, and JAK2 activation. Vanadate, however, reversed the Plumbagin-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that Plumbagin induced the expression of the protein tyrosine phosphatase, SHP-1, and silencing of the SHP-1 abolished the effect of Plumbagin. This agent also downregulated the expression of STAT3-regulated cyclin D1, Bcl-xL, and vascular endothelial growth factor; activated caspase-3; induced poly (ADP ribose) polymerase cleavage; and increased the sub-G(1) population of MM cells. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the Plumbagin-induced apoptosis. When compared with AG490, a rationally designed STAT3/JAK2 inhibitor, Plumbagin was found more potent in suppressing the proliferation of cells. Plumbagin also significantly potentiated the apoptotic effects of thalidomide and bortezomib in MM cells. Overall, these results suggest that the Plumbagin inhibits STAT3 activation pathway through the induction of SHP-1 and this may mediate the sensitization of STAT3 overexpressing cancers to chemotherapeutic agents.
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anti inflammatory effects of Plumbagin are mediated by inhibition of nf kappab activation in lymphocytes
International Immunopharmacology, 2009Co-Authors: Rahul Checker, Deepak Sharma, Santosh K Sandur, Shazia Khanam, T B PoduvalAbstract:Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), a quinone isolated from the roots of Plumbago zeylanica was recently reported to suppress the activation of NF-kappaB in tumor cells. NF-kappaB, a ubiquitous transcription factor, plays a central role in regulating diverse processes in leukocytes like cellular proliferation, expression of immunoregulatory genes and apoptosis during innate and adaptive immune responses. Consequently, Plumbagin might affect the biological functions of leukocytes participating in various immune responses. The present report describes novel immunomodulatory effects of Plumbagin. Plumbagin inhibited T cell proliferation in response to polyclonal mitogen Concanavalin A (Con A) by blocking cell cycle progression. It also suppressed expression of early and late activation markers CD69 and CD25 respectively, in activated T cells. At these immunosuppressive doses (up to 5 microM), Plumbagin did not reduce the viability of lymphocytes. Further, the inhibition of T cell proliferation by Plumbagin was accompanied by a decrease in the levels of Con A induced IL-2, IL-4, IL-6 and IFN-gamma cytokines. Similar immunosuppressive effects of Plumbagin on cytokine levels were seen in vivo. To characterize the mechanism of inhibitory action of Plumbagin, the mitogen induced IkappaB-alpha degradation and nuclear translocation of NF-kappaB was studied in lymphocytes. Plumbagin completely inhibited Con A induced IkappaB-alpha degradation and NF-kappaB activation. Further, Plumbagin prevented Graft Versus Host Disease-induced mortality in mice. To our knowledge this is the first report showing the immunomodulatory effects of Plumbagin in lymphocytes via modulation of NF-kappaB activation.
Bharat B Aggarwal - One of the best experts on this subject based on the ideXlab platform.
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5 hydroxy 2 methyl 1 4 naphthoquinone a vitamin k3 analogue suppresses stat3 activation pathway through induction of protein tyrosine phosphatase shp 1 potential role in chemosensitization
Molecular Cancer Research, 2010Co-Authors: Santosh K Sandur, Manoj K Pandey, Bokyung Sung, Bharat B AggarwalAbstract:The activation of signal transducers and activators of transcription 3 (STAT3) has been linked with carcinogenesis through survival, proliferation, and angiogenesis of tumor cells. Agents that can suppress STAT3 activation have potential not only for prevention but also for treatment of cancer. In the present report, we investigated whether 5-hydroxy-2-methyl-1,4-naphthoquinone (Plumbagin), an analogue of vitamin K, and isolated from chitrak (Plumbago zeylanica), an Ayurvedic medicinal plant, can modulate the STAT3 pathway. We found that Plumbagin inhibited both constitutive and interleukin 6-inducible STAT3 phosphorylation in multiple myeloma (MM) cells and this correlated with the inhibition of c-Src, Janus-activated kinase (JAK)1, and JAK2 activation. Vanadate, however, reversed the Plumbagin-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that Plumbagin induced the expression of the protein tyrosine phosphatase, SHP-1, and silencing of the SHP-1 abolished the effect of Plumbagin. This agent also downregulated the expression of STAT3-regulated cyclin D1, Bcl-xL, and vascular endothelial growth factor; activated caspase-3; induced poly (ADP ribose) polymerase cleavage; and increased the sub-G(1) population of MM cells. Consistent with these results, overexpression of constitutive active STAT3 significantly reduced the Plumbagin-induced apoptosis. When compared with AG490, a rationally designed STAT3/JAK2 inhibitor, Plumbagin was found more potent in suppressing the proliferation of cells. Plumbagin also significantly potentiated the apoptotic effects of thalidomide and bortezomib in MM cells. Overall, these results suggest that the Plumbagin inhibits STAT3 activation pathway through the induction of SHP-1 and this may mediate the sensitization of STAT3 overexpressing cancers to chemotherapeutic agents.
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Plumbagin 5 hydroxy 2 methyl 1 4 naphthoquinone suppresses nf κb activation and nf κb regulated gene products through modulation of p65 and iκbα kinase activation leading to potentiation of apoptosis induced by cytokine and chemotherapeutic agents
Journal of Biological Chemistry, 2006Co-Authors: Santosh K Sandur, Haruyo Ichikawa, Gautam Sethi, Kwang Seok Ahn, Bharat B AggarwalAbstract:Abstract Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-κB, suggesting Plumbagin might affect the NF-κB activation pathway. We found that Plumbagin inhibited NF-κB activation induced by TNF, and other carcinogens and inflammatory stimuli (e.g. phorbol 12-myristate 13-acetate, H2O2, cigarette smoke condensate, interleukin-1β, lipopolysaccharide, and okadaic acid). Plumbagin also suppressed the constitutive NF-κB activation in certain tumor cells. The suppression of NF-κB activation correlated with sequential inhibition of the tumor necrosis factor (TNF)-induced activation of IκBα kinase, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-κB-dependent reporter gene expression activated by TNF, TNFR1, TRAF2, NIK, IKK-β, and the p65 subunit of NF-κB. Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo. However, Plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine. Plumbagin down-regulated the expression of NF-κB-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-2), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by TNF and paclitaxel and inhibited cell invasion. Overall, our results indicate that Plumbagin is a potent inhibitor of the NF-κB activation pathway that leads to suppression of NF-κB-regulated gene products. This may explain its cell growth modulatory, anticarcinogenic, and radiosensitizing effects previously described.
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Plumbagin 5 hydroxy 2 methyl 1 4 naphthoquinone suppresses nf κb activation and nf κb regulated gene products through modulation of p65 and iκbα kinase activation leading to potentiation of apoptosis induced by cytokine and chemotherapeutic agents
Journal of Biological Chemistry, 2006Co-Authors: Santosh K Sandur, Haruyo Ichikawa, Gautam Sethi, Kwang Seok Ahn, Bharat B AggarwalAbstract:Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-kappaB, suggesting Plumbagin might affect the NF-kappaB activation pathway. We found that Plumbagin inhibited NF-kappaB activation induced by TNF, and other carcinogens and inflammatory stimuli (e.g. phorbol 12-myristate 13-acetate, H2O2, cigarette smoke condensate, interleukin-1beta, lipopolysaccharide, and okadaic acid). Plumbagin also suppressed the constitutive NF-kappaB activation in certain tumor cells. The suppression of NF-kappaB activation correlated with sequential inhibition of the tumor necrosis factor (TNF)-induced activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRAF2, NIK, IKK-beta, and the p65 subunit of NF-kappaB. Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo. However, Plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine. Plumbagin down-regulated the expression of NF-kappaB-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-2), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by TNF and paclitaxel and inhibited cell invasion. Overall, our results indicate that Plumbagin is a potent inhibitor of the NF-kappaB activation pathway that leads to suppression of NF-kappaB-regulated gene products. This may explain its cell growth modulatory, anticarcinogenic, and radiosensitizing effects previously described.
Tingting Tang - One of the best experts on this subject based on the ideXlab platform.
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Plumbagin ameliorates collagen induced arthritis by regulating treg th17 cell imbalances and suppressing osteoclastogenesis
Frontiers in Immunology, 2019Co-Authors: Tingyu Wang, Han Qiao, Zanjing Zhai, Jun Zhang, Xinyi Zheng, Niandong Qian, Hong Zhou, Tingting TangAbstract:Objective: Plumbago zeylanica L. (with Plumbagin as its active ingredients) has been used for centuries to treat conditions such as joint swelling, fractures, and bacterial infections, suggesting that it possesses anti-inflammatory and immunosuppressive properties. In the present study, we evaluated the potential anti-arthritic activity and related mechanisms of Plumbagin. Methods: Collagen-induced arthritis (CIA) was initiated in Wistar rats with collagen type II. Plumbagin (2 and 6 mg/kg) was orally administered to rats with CIA from day 12 to day 32 post immunization. The effects of Plumbagin on arthritis progression were assessed by paw swelling, clinical scoring, and histologic analysis. The percentage of Treg and Th17 were defined by flow cytometry or immunofluorescence (IF) staining. Bone erosion and resorption were assessed by micro-CT and histomorphometric analysis. Osteoclast differentiation was further determined by in vitro osteoclastogenesis assay. The molecular docking assay was used to determine the potential binding site of Plumbagin. Results: Treatment with Plumbagin significantly inhibited arthritis development, as well as suppressed the local and systemic inflammation. Plumbagin reciprocally regulated pro-inflammatory Th17 cell and immunosuppressive Treg cell populations. In addition, Plumbagin protected inflammation-induced bone loss by inhibiting osteoclast formation and activity. Plumbagin markedly suppressed RANKL-stimulated osteoclast-specific gene expression by repressing NF-κB signaling activation and MAP kinase phosphorylation. Further study via molecular docking assay demonstrated that Plumbagin bound to MET169 of JNK kinase and LYS138 and SER183 of p38 kinase. Conclusion: Plumbagin not only attenuates the immune-induced arthritis by inhibiting inflammation, but also protects bone erosion by directly inhibiting osteoclast formation and activity. These data suggest Plumbagin is a promising new candidate drug for treating inflammatory joint diseases.
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Plumbagin Ameliorates Collagen-Induced Arthritis by Regulating Treg/Th17 Cell Imbalances and Suppressing Osteoclastogenesis
Frontiers Media S.A., 2019Co-Authors: Tingyu Wang, Han Qiao, Zanjing Zhai, Jun Zhang, Xinyi Zheng, Niandong Qian, Hong Zhou, Tingting TangAbstract:Objective: Plumbago zeylanica L. (with Plumbagin as its active ingredients) has been used for centuries to treat conditions such as joint swelling, fractures, and bacterial infections, suggesting that it possesses anti-inflammatory and immunosuppressive properties. In the present study, we evaluated the potential anti-arthritic activity and related mechanisms of Plumbagin.Methods: Collagen-induced arthritis (CIA) was initiated in Wistar rats with collagen type II. Plumbagin (2 and 6 mg/kg) was orally administered to rats with CIA from day 12 to day 32 post immunization. The effects of Plumbagin on arthritis progression were assessed by paw swelling, clinical scoring, and histologic analysis. The percentage of Treg and Th17 were defined by flow cytometry or immunofluorescence (IF) staining. Bone erosion and resorption were assessed by micro-CT and histomorphometric analysis. Osteoclast differentiation was further determined by in vitro osteoclastogenesis assay. The molecular docking assay was used to determine the potential binding site of Plumbagin.Results: Treatment with Plumbagin significantly inhibited arthritis development, as well as suppressed the local and systemic inflammation. Plumbagin reciprocally regulated pro-inflammatory Th17 cell and immunosuppressive Treg cell populations. In addition, Plumbagin protected inflammation-induced bone loss by inhibiting osteoclast formation and activity. Plumbagin markedly suppressed RANKL-stimulated osteoclast-specific gene expression by repressing NF-κB signaling activation and MAP kinase phosphorylation. Further study via molecular docking assay demonstrated that Plumbagin bound to MET169 of JNK kinase and LYS138 and SER183 of p38 kinase.Conclusion: Plumbagin not only attenuates the immune-induced arthritis by inhibiting inflammation, but also protects bone erosion by directly inhibiting osteoclast formation and activity. These data suggest Plumbagin is a promising new candidate drug for treating inflammatory joint diseases
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Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of mice
Acta Pharmacologica Sinica, 2014Co-Authors: Wei Yan, Tingyu Wang, Zanjing Zhai, Qiming Fan, Tingting TangAbstract:To investigate the effects of Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, on human breast cancer cell growth and the cancer cell-induced osteolysis in the bone microenvironment of mice. Human breast cancer cell subline MDA-MB-231SA with the ability to spread and grow in the bone was tested. The cell proliferation was determined using the CCK-8 assay. Apoptosis was detected with Annexin V/PI double-labeled flow cytometry. Red fluorescent protein-labeled MDA-MB-231SArfp cells were injected into the right tibia of female BALB/c-nu/nu mice. Three days after the inoculation, the mice were injected with Plumbagin (2, 4, or 6 mg/kg, ip) 5 times per week for 7 weeks. The growth of the tumor cells was monitored using an in vivo imaging system. After the mice were sacrificed, the hind limbs were removed for radiographic and histological analyses. Plumbagin (2.5–20 μmol/L) concentration-dependently inhibited the cell viability and induced apoptosis of MDA-MB-231SA cells in vitro (the IC50 value of inhibition of cell viability was 14.7 μmol/L). Administration of Plumbagin to breast cancer bearing mice delayed the tumor growth by 2–3 weeks and reduced the tumor volume by 44%–74%. The in vivo imaging study showed that Plumbagin dose-dependently inhibited MDA-MB-231SArfp cell growth in bone microenvironment. Furthermore, X-ray images and micro-CT study demonstrated that Plumbagin reduced bone erosion area and prevented a decrease in bone tissue volume. Histological studies showed that Plumbagin dose-dependently inhibited the breast cancer cell growth, enhanced the cell apoptosis and reduced the number of TRAcP-positive osteoclasts. Plumbagin inhibits the cell growth and induces apoptosis in human breast cancer cells in mice bone microenvironment, leading to significant reduction in osteolytic lesions caused by the tumor cells.
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suppressive effects of Plumbagin on invasion and migration of breast cancer cells via the inhibition of stat3 signaling and down regulation of inflammatory cytokine expressions
Bone research, 2013Co-Authors: Wei Yan, Tingyu Wang, Han Qiao, Zanjing Zhai, Yunyun Liu, Tingting TangAbstract:Objective: The aim of this study was to investigate the effects of Plumbagin (PL), a naphthoquinone derived from the medicinal plant plumbago zeylanica, on the invasion and migration of human breast cancer cells. Methods: Human breast cancer MDA-MB-231SArfp cells were treated with different concentrations of Plumbagin for 24 h. The effects of Plumbagin on the migration and invasion were observed by a transwell method. The expressions of IL-1α, IL-1β, IL-6, IL-8, TGF-β, TNFα, MMP-2 and MMP-9 mRNA in MDA-MB-231SArfp cells were detected using Real-Time PCR. MDA-MB-231SArfp cells were treated with Plumbagin at different concentrations for 45 minutes. The activation of STAT3 was detected by western blot. Following this analysis, STAT3 in MDA-MB-231SArfp cells was knocked out using specific siRNA. mRNA levels of IL-1α, TGF-β, MMP-2 and MMP-9 were then detected. Consequently, MDA-MB-231SArfp cells were injected intracardially into BALB/c nude mice to construct a breast cancer bone metastatic model. The mice were injected intraperitoneally with Plumbagin. Non-invasive in vivo monitoring, X-ray imaging and histological staining were performed to investigate the effects of Plumbagin on the invasion and migration of breast cancer cells in vivo. Results: The in vitro results showed that Plumbagin could suppress the migration and invasion of breast cancer cells and down-regulate mRNA expressions of IL-1α, TGF-β, MMP-2 and MMP-9. Western blotting demonstrated that Plumbagin inhibited the activation of STAT3 signaling in MDA-MB-231SArfp cells. The inactivation of STAT3 was found to have an inhibitory effect on the expressions of IL-1α, TGF-β, MMP-2 and MMP-9. In vivo studies showed that Plumbagin inhibited the metastasis of breast cancer cells and decreased osteolytic bone metastases, as well as the secretion of MMP-2 and MMP-9 by tumor cells at metastatic lesions. Conclusions: Plumbagin can suppress the invasion and migration of breast cancer cells via the inhibition of STAT3 signaling and by downregulation of IL-1α, TGF-β, MMP-2 and MMP-9.
G Srinivas - One of the best experts on this subject based on the ideXlab platform.
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radiosensitizing effects of Plumbagin in cervical cancer cells is through modulation of apoptotic pathway
Molecular Carcinogenesis, 2008Co-Authors: Sreekala Nair, Priya Srinivas, G Srinivas, Raghu Ram K Nair, Radhakrishna M PillaiAbstract:Radiotherapy is the primary line of cancer treatment for cervical cancer and is known to induce cell death in tumors. Radiotherapy is however limited by the total dose that can be given without damaging normal tissue. Plumbagin, a naturally occurring naphthaquinone, has been reported to have free radical producing properties. Hence we hypothesized that Plumbagin could also have properties that could modify effects of radiation on cervical cancer cells. Radiation in combination with Plumbagin may thus have treatment augmenting effects. Results from our studies have shown that a lower dose of radiation in combination with Plumbagin could induce apoptosis more effectively compared to a higher dose of radiation alone. Plumbagin in combination with 2 Gy of radiation was very effective in inducing apoptosis, when compared to a higher radiation dose of 10 Gy alone. This combination also showed a fivefold increase in the activation of caspase 3 in C33A cells. Activation of effector caspases confirms that the induction of apoptosis by irradiation and Plumbagin involves caspase-dependent pathways. Expression of apoptotic regulatory molecules Bcl-2, Bax and Survivin was also modulated by Plumbagin in combination with radiation. In summary, this study shows that a combination of Plumbagin and radiation augmented cell growth inhibition compared to higher radiation dose alone, thus indicating that Plumbagin may be a potential radiosensitizer acting through the induction of apoptosis.
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estrogen dependent cell signaling and apoptosis in brca1 blocked bg1 ovarian cancer cells in response to Plumbagin and other chemotherapeutic agents
Annals of Oncology, 2007Co-Authors: K A Thasni, G Srinivas, S N Rakesh, G Rojini, T Ratheeshkumar, S PriyaAbstract:Abstract Background Cellular response to chemotherapeutic drugs in the absence of BRCA1 either completely or partially had drawn less attention. The present study evaluated whether there is a differential inhibition of cell growth by selected compounds with respect to BRCA1 status in estrogen receptor (ER)-positive ovarian cancer cells. Materials and methods The BG1 ovarian cancer cells used in the experiments were antisensely blocked with BRCA1 gene. Growth inhibition and apoptotic induction were analyzed to evaluate the cytotoxic effects. Small interfering RNA (SiRNA) transfection, western blot analysis, RT–PCR analysis and molecular modeling were carried out to analyze the estrogen-dependent action of Plumbagin. Results Although we found that all the compounds studied induce apoptosis, the induction was in the order of Plumbagin > doxorubicin > tamoxifen > cisplatin. Plumbagin can bind to the active site of ER-α. Plumbagin, however, induced ER-α 46 kDa truncated isoform, which was found abundantly preempted in the cytoplasm compared with a 66-kDa full-length isoform. The truncated isoform is known to inhibit classical ER-α signaling pathways. SiRNA-transfected cells for ER-α exhibited lower cytotoxicity upon Plumbagin treatment than the control-transfected cells. Conclusion Taken together, this study indicates that Plumbagin has chemotherapeutic potential in BRCA1-mutated/defective ER-positive cancers.
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Plumbagin induces reactive oxygen species which mediate apoptosis in human cervical cancer cells
Molecular Carcinogenesis, 2004Co-Authors: Priya Srinivas, Gokul Gopinath, Asoke Banerji, Abhilash Dinakar, G SrinivasAbstract:There is an emerging evidence that Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone) may have potential as a chemotherapeutic agent. However, the growth inhibitory mechanisms of Plumbagin have remained unexplored. The aim of the study was to determine whether Plumbagin-induced cell death in human cervical cancer cell line, ME-180, exhibited biochemical characteristics of apoptosis and to check whether N-acetyl-l-cysteine (NAC), which is a free radical scavenger, can reverse the cytotoxic effects of Plumbagin. It can be concluded from the results that Plumbagin inhibits the growth of ME-180 cells in a concentration and time-dependent manner. The cytotoxic effect of Plumbagin induced cell death is through the generation of reactive oxygen species (ROS) and subsequent induction of apoptosis as demonstrated by the present data. Treatment of cells with Plumbagin caused loss of mitochondrial membrane potential (DeltaPsi(m)), and morphological changes characteristic of apoptosis, such as the translocation of phosphatidyl serine, nuclear condensation, and DNA fragmentation. Moreover, Plumbagin-induced apoptosis involved release of mitochondrial cytochrome c and apoptosis inducing factor (AIF), thus activation of caspase-dependent and -independent pathways, as shown by the Plumbagin-mediated activation of caspase-3 and -9. Our results also show that pretreatment of ME-180 cells with NAC blocks Plumbagin-induced loss of DeltaPsi(m) and subsequent release of cytochrome c, AIF, and caspase-9 and -3 activation, thus inhibiting the apoptotic ability of Plumbagin.
P J Lohoue - One of the best experts on this subject based on the ideXlab platform.
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in vitro antifungal activity of extract and Plumbagin from the stem bark of diospyros crassiflora hiern ebenaceae
Phytotherapy Research, 2007Co-Authors: Jean Paul Dzoyem, J G Tangmouo, David Lontsi, Francoisxavier Etoa, P J LohoueAbstract:In this study the methanol/dichloromethane (1:1) extract and Plumbagin isolated from extract of stem barks of Diospyros crassiflora were tested for their antifungal activity against 12 strains of yeast pathogens and filamentous fungi: Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Cryptococcus neoformans, Aspergillus niger, Aspergillus flavus, Alternaria sp., Cladosporium sp., Geotrichum candidum, Fusarium sp. and Penicillium sp. The growth of all fungi strains tested was inhibited by the extract and Plumbagin. The diameter of inhibition zones varied from 12 to 18 mm and from 21 to 35 mm for the extract and Plumbagin, respectively. The MIC values ranged from 12.5 to 25 mg/mL for the extract and 0.78–3.12 µg/mL for Plumbagin. It is therefore suggested that extracts from the stem bark of Diospyros crassiflora could be used traditionally in the treatment of fungal infections. Compared with ketoconazole used as a standard antifungal, Plumbagin could be considered as a promising antifungal agent. Copyright © 2007 John Wiley & Sons, Ltd.
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in vitro antifungal activity of extract and Plumbagin from the stem bark of diospyros crassiflora hiern ebenaceae
Phytotherapy Research, 2007Co-Authors: Jean Paul Dzoyem, J G Tangmouo, David Lontsi, Francoisxavier Etoa, P J LohoueAbstract:In this study the methanol/dichloromethane (1:1) extract and Plumbagin isolated from extract of stem barks of Diospyros crassiflora were tested for their antifungal activity against 12 strains of yeast pathogens and filamentous fungi: Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Cryptococcus neoformans, Aspergillus niger, Aspergillus flavus, Alternaria sp., Cladosporium sp., Geotrichum candidum, Fusarium sp. and Penicillium sp. The growth of all fungi strains tested was inhibited by the extract and Plumbagin. The diameter of inhibition zones varied from 12 to 18 mm and from 21 to 35 mm for the extract and Plumbagin, respectively. The MIC values ranged from 12.5 to 25 mg/mL for the extract and 0.78-3.12 microg/mL for Plumbagin. It is therefore suggested that extracts from the stem bark of Diospyros crassiflora could be used traditionally in the treatment of fungal infections. Compared with ketoconazole used as a standard antifungal, Plumbagin could be considered as a promising antifungal agent.