Shweta Kapoor

Bharathiar University, Koyambattūr, Tamil Nādu, India

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Publications (14)49.2 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background:The increasing usage of statins (the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) has revealed a number of unexpected beneficial effects, including a reduction in cancer risk.Methods:We investigated the direct anticancer effects of different statins approved for clinical use on human breast and brain cancer cells. We also explored the effects of statins on cancer cells using in silico simulations.Results:In vitro studies showed that cerivastatin, pitavastatin, and fluvastatin were the most potent anti-proliferative, autophagy inducing agents in human cancer cells including stem cell-like primary glioblastoma cell lines. Consistently, pitavastatin was more effective than fluvastatin in inhibiting U87 tumour growth in vivo. Intraperitoneal injection was much better than oral administration in delaying glioblastoma growth. Following statin treatment, tumour cells were rescued by adding mevalonate and geranylgeranyl pyrophosphate. Knockdown of geranylgeranyl pyrophosphate synthetase-1 also induced strong cell autophagy and cell death in vitro and reduced U87 tumour growth in vivo. These data demonstrate that statins main effect is via targeting the mevalonate synthesis pathway in tumour cells.Conclusions:Our study demonstrates the potent anticancer effects of statins. These safe and well-tolerated drugs need to be further investigated as cancer chemotherapeutics in comprehensive clinical studies.British Journal of Cancer advance online publication, 5 August 2014; doi:10.1038/bjc.2014.431 www.bjcancer.com.
    British journal of cancer. 08/2014;
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    ABSTRACT: Glioblastoma (GBM) is an aggressive disease associated with poor survival. It is essential to account for the complexity of GBM biology to improve diagnostic and therapeutic strategies. This complexity is best represented by the increasing amounts of profiling ("omics") data available due to advances in biotechnology. The challenge of integrating these vast genomic and proteomic data can be addressed by a comprehensive systems modeling approach.
    Journal of translational medicine. 01/2014; 12(1):128.
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    ABSTRACT: Introduction Ursolic acid (UA) is a pentacyclic triterpene acid present in many plants, including apples, basil, cranberries, and rosemary. UA suppresses proliferation and induces apoptosis in a variety of tumor cells via inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Given that single agent therapy is a major clinical obstacle to overcome in the treatment of cancer, we sought to enhance the anti-cancer efficacy of UA through rational design of combinatorial therapeutic regimens that target multiple signaling pathways critical to carcinogenesis. Methodology Using a predictive simulation-based approach that models cancer disease physiology by integrating signaling and metabolic networks, we tested the effect of UA alone and in combination with 100 other agents across cell lines from colorectal cancer, non-small cell lung cancer and multiple myeloma. Our predictive results were validated in vitro using standard molecular assays. The MTT assay and flow cytometry were used to assess cellular proliferation. Western blotting was used to monitor the combinatorial effects on apoptotic and cellular signaling pathways. Synergy was analyzed using isobologram plots. Results We predictively identified c-Jun N-terminal kinase (JNK) as a pathway that may synergistically inhibit cancer growth when targeted in combination with NFκB. UA in combination with the pan-JNK inhibitor SP600125 showed maximal reduction in viability across a panel of cancer cell lines, thereby corroborating our predictive simulation assays. In HCT116 colon carcinoma cells, the combination caused a 52% reduction in viability compared with 18% and 27% for UA and SP600125 alone, respectively. In addition, isobologram plot analysis reveals synergy with lowered doses of the drugs in combination. The combination synergistically inhibited proliferation and induced apoptosis as evidenced by an increase in the percentage sub-G1 phase cells and cleavage of caspase 3 and poly ADP ribose polymerase (PARP). Combination treatment resulted in a significant reduction in the expression of cyclin D1 and c-Myc as compared with single agent treatment. Conclusions Our findings underscore the importance of targeting NFκB and JNK signaling in combination in cancer cells. These results also highlight and validate the use of predictive simulation technology to design therapeutics for targeting novel biological mechanisms using existing or novel chemistry.
    Journal of Cancer. 01/2014; 5(6):406-16.
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    ABSTRACT: Aberrant activation of signal transducer and activators of transcription 3 (STAT3) is frequently encountered and promotes proliferation, survival, metastasis and angiogenesis in hepatocellular carcinoma (HCC). In the present study, we investigated whether emodin mediates its effect through interference with the STAT3 activation pathway in HCC. The effect of emodin on STAT3 activation, associated protein kinases, and apoptosis was investigated using various HCC cell lines. Additionally we also explicitly tested if emodin effects were mediated by STAT3 inhibition using a predictive tumor technology. The in vivo effect of emodin on the orthotopic mouse model was also examined. We found that emodin suppressed STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the modulation of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Vanadate treatment reversed emodin-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that emodin induced the expression of tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Interestingly, deletion of SHP-1 gene by siRNA abolished the ability of this quinone to inhibit STAT3 activation. Finally, when administered i.p., emodin inhibited the growth of human HCC orthotopic tumors in male athymic nu/nu mice and STAT3 activation in tumor tissues. Overall, our results suggest that emodin is mediating its effects predominantly through inhibition of STAT3 signaling cascade and thus has an enormous potential for the treatment cancers harboring constitutively activated STAT3.
    British Journal of Pharmacology 07/2013; · 5.07 Impact Factor
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    ABSTRACT: Constitutive activation of STAT3 is frequently observed and closely linked with proliferation, survival, invasion, metastasis and angiogenesis in tumor cells. In the present study, we investigated whether β-caryophyllene oxide (CPO), a sesquiterpene isolated primarily from the essential oils of medicinal plants such as guava (Psidium guajava), and oregano (Origanum vulgare L.), can mediate its effect through interference with the STAT3 activation pathway in cancer cells. The effect of CPO on STAT3 activation, associated protein kinases and phosphatase, STAT3-regulated gene products and apoptosis was investigated using both functional proteomics tumor pathway technology platform and different tumor cell lines. We found that CPO suppressed constitutive STAT3 activation in multiple myeloma (MM), breast and prostate cancer cell lines, with a significant dose- and time-dependent effects observed in MM cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src and JAK1/2. Also, vanadate treatment reversed CPO-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that CPO induced the expression of tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Interestingly, deletion of SHP-1 gene by siRNA abolished the ability of CPO to inhibit STAT3 activation. The inhibition of STAT3 activation by CPO inhibited proliferation, induced apoptosis and abrogated the invasive potential of tumor cells. Our results suggest for the first time that CPO is a novel blocker of STAT3 signaling cascade and thus has an enormous potential for the treatment of various cancers harboring constitutively activated STAT3. © 2013 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 06/2013; · 4.27 Impact Factor
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    ABSTRACT: Gastric cancer (GC) is one of the most lethal malignancies and the second-most common cause of cancer-related deaths. Though treatment options such as chemotherapy, radiotherapy, and surgery have led to a decline in the incidence of GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of Isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin on the PPAR-g signaling cascade using proteomics technology platform, GC cell lines and xenograft mice model. We observed that IH exerted strong anti-proliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells which could be reversed in the presence of PPAR-g inhibitor. We found that IH increased PPAR-g activity and modulated the expression of PPAR-g regulated genes in GC cells. Also, the increase in PPAR-g activity was reversed in the presence of PPAR-g specific inhibitor and a mutated PPAR-g dominant negative plasmid, supporting our hypothesis that IH can act as a ligand of PPAR-g. Using molecular docking analysis, we demonstrate that IH formed interactions with 7 polar residues and 6 non-polar residues within the ligand-binding pocket of PPAR-g that are reported to be critical for its activity and could competitively bind to PPAR-g. IH significantly increased the expression of PPAR-g in tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that anti-tumor effects of IH may be mediated through modulation of the PPAR-g activation pathway in GC.
    Journal of Biological Chemistry 09/2012; · 4.65 Impact Factor
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    ABSTRACT: Increasing evidence indicates that the interaction between the CXC chemokine receptor-4 (CXCR4) and its ligand CXCL12 is critical in the process of metastasis that accounts for more than 90% of cancer-related deaths. Thus, novel agents that can downregulate the CXCR4/CXCL12 axis have therapeutic potential in inhibiting cancer metastasis. In this report, we investigated the potential of an agent, plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), for its ability to modulate CXCR4 expression and function in various tumor cells using Western blot analysis, DNA binding assay, transient transfection, real time PCR analysis, chromatin immunoprecipitation, and cellular migration and invasion assays. We found that plumbagin downregulated the expression of CXCR4 in breast cancer cells irrespective of their HER2 status. The decrease in CXCR4 expression induced by plumbagin was not cell type-specific as the inhibition also occurred in gastric, lung, renal, oral, and hepatocellular tumor cell lines. Neither proteasome inhibition nor lysosomal stabilization had any effect on plumbagin-induced decrease in CXCR4 expression. Detailed study of the underlying molecular mechanism(s) revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, inhibition of NF-κB activation, and suppression of chromatin immunoprecipitation activity. In addition, using a virtual, predictive, functional proteomics-based tumor pathway platform, we tested the hypothesis that NF-κB inhibition by plumbagin causes the decrease in CXCR4 and other metastatic genes. Suppression of CXCR4 expression by plumbagin was found to correlate with the inhibition of CXCL12-induced migration and invasion of both breast and gastric cancer cells. Overall, our results indicate, for the first time, that plumbagin is a novel blocker of CXCR4 expression and thus has the potential to suppress metastasis of cancer.
    Molecular Cancer 09/2011; 10:107. · 5.13 Impact Factor
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    ABSTRACT: The activation of signal transducers and activators of transcription 3 (STAT3) has been closely linked with the proliferation, survival, invasion, and angiogenesis of hepatocellular carcinoma (HCC) and represents an attractive target for therapy. In the present report, we investigated whether honokiol mediates its effect through interference with the STAT3 activation pathway. The effect of honokiol on STAT3 activation, associated protein kinases, and phosphatase, STAT3-regulated gene products and apoptosis was investigated using both functional proteomics tumor pathway technology platform and different HCC cell lines. We found that honokiol inhibited both constitutive and inducible STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Vanadate treatment reversed honokiol-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that honokiol induced the expression of tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Moreover, deletion of SHP-1 gene by siRNA abolished the ability of honokiol to inhibit STAT3 activation. The inhibition of STAT3 activation by honokiol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Finally, honokiol inhibited proliferation and significantly potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, the results suggest that honokiol is a novel blocker of STAT3 activation and may have a great potential for the treatment of HCC and other cancers.
    Journal of Cellular Physiology 07/2011; 227(5):2184-95. · 4.22 Impact Factor
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    ABSTRACT: Small molecule inhibitors of epidermal growth factor receptors (EGFR) have been found to show a good initial response in cancer patients but during the course of treatment, patients develop resistance after a few weeks of time. Development of secondary mutations or over-activation of insulin like growth factor (IGF-1R) pathway are a few of the several mechanisms proposed to explain the resistance. To study the effect of dual inhibition of EGFR and IGF-1R in overcoming the resistance, three strategies were envisaged and are reported in this manuscript: 1) a virtual predictive tumor model, 2) in vitro experimental data using a combination of EGFR and IGF-1R inhibitors and 3) in vitro experimental data using in house dual inhibitors. Findings reported in this manuscript suggest that simultaneous inhibition of IGF-1R and EGFR either by combination of two inhibitors or by dual kinase inhibitors is more efficacious compared to single agents. In vitro cell based experiments conducted using epidermoid cancer cell line, A431 and an EGFR mutant cell line, H1975 along with virtual predictions reported here suggests that dual inhibition of EGFR and IGF-1R is a viable approach to overcome EGFR resistance.
    European journal of pharmacology 06/2011; 667(1-3):56-65. · 2.59 Impact Factor
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    ABSTRACT: Activation of pro-inflammatory transcription factors NF-κB and signal transducer and activator of transcription 3 (STAT3) is one of the major contributors to both pathogenesis and chemoresistance in multiple myeloma (MM), which results in high mortality rate. Thus, in the present study, we investigated whether celastrol could suppress the proliferation and induce chemosensitization of MM cells by interfering with NF-κB and STAT3 activation pathways. The effects of celastrol were investigated using both a virtual predictive tumour cell system and different MM cell lines resistant to doxorubicin, melphalan and bortezomib. Celastrol inhibited the proliferation of MM cell lines regardless of whether they were sensitive or resistant to bortezomib and other conventional chemotherapeutic drugs. It also synergistically enhanced the apoptotic effects of thalidomide and bortezomib. This correlated with the down-regulation of various proliferative and anti-apoptotic gene products including cyclin D1, Bcl-2, Bcl-xL, survivin, XIAP and Mcl-1. These effects of celastrol were mediated through suppression of constitutively active NF-κB induced by inhibition of IκBα kinase activation; and the phosphorylation of IκBα and of p65. Celastrol also inhibited both the constitutive and IL6-induced activation of STAT3, which induced apoptosis as indicated by an increase in the accumulation of cells in the sub-G1 phase, an increase in the expression of pro-apoptotic proteins and activation of caspase-3. Thus, based on our experimental findings, we conclude that celastrol may have great potential as a treatment for MM and other haematological malignancies.
    British Journal of Pharmacology 04/2011; 164(5):1506-21. · 5.07 Impact Factor
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    ABSTRACT: Activation of transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) is frequently observed in prostate cancer and has been linked with tumor cell proliferation, invasion, metastasis, and angiogenesis. In this study, we investigated the effect of ursolic acid (UA) on NF-κB and STAT3 signaling pathways in both androgen-independent (DU145) and androgen-dependent (LNCaP) prostate cancer cell lines and also prospectively tested the hypothesis of NF-κB and STAT3 inhibition using a virtual predictive functional proteomics tumor pathway technology platform. We found that UA inhibited constitutive and TNF-α-induced activation of NF-κB in DU145 and LNCaP cells in a dose-dependent manner. The suppression was mediated through the inhibition of constitutive and TNF-α-induced IκB kinase (IKK) activation, phosphorylation of IκBα and p65 and NF-κB-dependent reporter activity. Furthermore, UA suppressed both constitutive and inducible STAT3 activation in prostate cancer cells concomitant with suppression of activation of upstream kinases (Src and JAK2) and STAT3-dependent reporter gene activity. UA also downregulated the expression of various NF-κB and STAT3 regulated gene products involved in proliferation, survival, and angiogenesis and induced apoptosis in both cells lines as evidenced by DNA fragmentation and annexin V staining. In vivo, UA (200 mg/kg b.w.) treated for 6 weeks inhibited the growth of DU145 cells in nude mice without any significant effect on body weight. Overall, our results from experimental and predictive studies suggest that UA mediates its anti-tumor effects through suppression of NF-κB and STAT3 pathways in prostate cancer.
    Journal of Molecular Medicine 04/2011; 89(7):713-27. · 4.77 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third cause of global cancer mortality. Increasing evidence suggest that STAT3 is a critical mediator of oncogenic signaling in HCC and controls the expression of several genes involved in proliferation, survival, metastasis, and angiogenesis. Thus, the novel agents that can suppress STAT3 activation have potential for both prevention and treatment of HCC. The effect of butein on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was investigated. The in vivo effect of butein on the growth of human HCC xenograft tumors in male athymic nu/nu mice was also examined. We tested an agent, butein, for its ability to suppress STAT3 activation in HCC cells and nude mice model along with prospectively testing the hypothesis of STAT3 inhibition in a virtual predictive functional proteomics tumor pathway technology platform. We found that butein inhibited both constitutive and inducible STAT3 activation in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src and Janus-activated kinase 2. Butein inhibited proliferation and significantly potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. When administered intraperitoneally, butein inhibited the growth of human HCC xenograft tumors in male athymic nu/nu mice. Overall, cumulative results from experimental and predictive studies suggest that butein exerts its antiproliferative and proapoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo.
    Clinical Cancer Research 12/2010; 17(6):1425-39. · 7.84 Impact Factor
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    ABSTRACT: The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway mediates multiple myeloma (MM) cell proliferation, survival, and development of drug resistance, underscoring the role of mTOR inhibitors, such as rapamycin, with potential anti-MM activity. However, recent data show a positive feedback loop from mTOR/S6K1 to Akt, whereby Akt activation confers resistance to mTOR inhibitors. We confirmed that suppression of mTOR signaling in MM cells by rapamycin was associated with upregulation of Akt phosphorylation. We hypothesized that inhibiting this positive feedback by a potent Akt inhibitor perifosine would augment rapamycin-induced cytotoxicity in MM cells. Perifosine inhibited rapamycin-induced phosphorylated Akt, resulting in enhanced cytotoxicity in MM.1S cells even in the presence of interleukin-6, insulin-like growth factor-I, or bone marrow stromal cells. Moreover, rapamycin-induced autophagy in MM.1S MM cells, as evidenced by electron microscopy and immunocytochemistry, was augmented by perifosine. Combination therapy increased apoptosis detected by Annexin V/propidium iodide analysis and caspase/poly(ADP-ribose) polymerase cleavage. Importantly, in vivo antitumor activity and prolongation of survival in a MM mouse xenograft model after treatment was enhanced with combination of nanoparticle albumin-bound-rapamycin and perifosine. Utilizing the in silico predictive analysis, we confirmed our experimental findings of this drug combination on PI3K, Akt, mTOR kinases, and the caspases. Our data suggest that mutual suppression of the PI3K/Akt/mTOR pathway by rapamycin and perifosine combination induces synergistic MM cell cytotoxicity, providing the rationale for clinical trials in patients with relapsed/refractory MM. Mol Cancer Ther; 9(4); 963-75. (c)2010 AACR.
    Molecular Cancer Therapeutics 04/2010; 9(4):963-75. · 5.60 Impact Factor
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    ABSTRACT: Hsp90 is an ATP-dependent molecular chaperone that regulates key signaling proteins and thereby impacts cell growth and development. Chaperone cycle of Hsp90 is regulated by ATP binding and hydrolysis through its intrinsic ATPase activities, which is in turn modulated by interaction with its co-chaperones. Hsp90 ATPase activity varies in different organisms and is known to be increased in tumor cells. In this study we have quantitatively analyzed the impact of increasing Hsp90 ATPase activity on the activities of its clients through a virtual prototyping technology, which comprises a dynamic model of Hsp90 interaction with clients involved in proliferation pathways. Our studies highlight the importance of increased ATPase activity of Hsp90 in cancer cells as the key modulator for increased proliferation and survival. A tenfold increase in ATPase activity of Hsp90 often seen in cancer cells increases the levels of active client proteins such as Akt-1, Raf-1 and Cyclin D1 amongst others to about 12-, 8- and 186-folds respectively. Additionally we studied the effect of a competitive inhibitor of Hsp90 activity on the reduction in the client protein levels. Virtual prototyping experiments corroborate with findings that the drug has almost 10- to 100-fold higher affinity as indicated by a lower IC(50) value (30-100 nM) in tumor cells with higher ATPase activity. The results also indicate a 15- to 25-fold higher efficacy of the inhibitor in reducing client levels in tumor cells. This analysis provides mechanistic insights into the links between increased Hsp90 ATPase activity, tumor phenotype and the hypersensitivity of tumor Hsp90 to inhibition by ATP analogs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11693-009-9046-3) contains supplementary material, which is available to authorized users.
    Systems and Synthetic Biology 10/2009; 4(1):25-33.

Publication Stats

197 Citations
49.20 Total Impact Points

Institutions

  • 2013
    • Bharathiar University
      Koyambattūr, Tamil Nādu, India
  • 2011–2013
    • Cellworks Research
      Bengalūru, Karnātaka, India
  • 2010–2012
    • National University of Singapore
      • Department of Pharmacology
      Singapore, Singapore