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Smiti V. Gupta - One of the best experts on this subject based on the ideXlab platform.

  • delta tocotrienol suppresses notch 1 pathway by upregulating mir 34a in nonsmall cell lung cancer cells
    International Journal of Cancer, 2012
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Arvind Goja, Smiti V. Gupta
    Abstract:

    MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating various cellular functions by transcriptional silencing. miRNAs can function as either oncogenes or tumor suppressors (oncomirs), depending on cancer types. In our study, using miRNA microarray, we observed that downregulation of the Notch-1 pathway, by Delta-Tocotrienol, correlated with upregulation of miR-34a, in nonsmall cell lung cancer cells (NSCLC). Moreover, re-expression of miR-34a by transfection in NSCLC cells resulted in inhibition of cell growth and invasiveness, induction of apoptosis and enhanced p53 activity. Furthermore, cellular mechanism studies revealed that induction of miR-34a decreased the expression of Notch-1 and its downstream targets including Hes-1, Cyclin D1, Survivin and Bcl-2. Our findings suggest that Delta-Tocotrienol is a nontoxic activator of mir-34a which can inhibit NSCLC cell proliferation, induce apoptosis and inhibit invasion, and thus offering a potential starting point for the design of novel anticancer agents.

  • Delta‐tocotrienol suppresses Notch‐1 pathway by upregulating miR‐34a in nonsmall cell lung cancer cells
    International journal of cancer, 2012
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Arvind Goja, Smiti V. Gupta
    Abstract:

    MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating various cellular functions by transcriptional silencing. miRNAs can function as either oncogenes or tumor suppressors (oncomirs), depending on cancer types. In our study, using miRNA microarray, we observed that downregulation of the Notch-1 pathway, by Delta-Tocotrienol, correlated with upregulation of miR-34a, in nonsmall cell lung cancer cells (NSCLC). Moreover, re-expression of miR-34a by transfection in NSCLC cells resulted in inhibition of cell growth and invasiveness, induction of apoptosis and enhanced p53 activity. Furthermore, cellular mechanism studies revealed that induction of miR-34a decreased the expression of Notch-1 and its downstream targets including Hes-1, Cyclin D1, Survivin and Bcl-2. Our findings suggest that Delta-Tocotrienol is a nontoxic activator of mir-34a which can inhibit NSCLC cell proliferation, induce apoptosis and inhibit invasion, and thus offering a potential starting point for the design of novel anticancer agents.

  • Delta-Tocotrienol augments cisplatin-induced suppression of non-small cell lung cancer cells via inhibition of the Notch-1 pathway
    Anticancer research, 2012
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Smiti V. Gupta
    Abstract:

    Non-small cell lung cancer (NSCLC), accounting for 80% of lung cancers, is the leading cause of all cancer deaths. Previously, we demonstrated that Delta-Tocotrienol inhibits NSCLC cell proliferation, invasion and induces apoptosis by down-regulation of the Notch-1 signaling pathway. The objective of this study was to investigate whether Delta-Tocotrienol, could enhance the anticancer effects of cisplatin. Treatment with a combination of Delta-Tocotrienol and cisplatin resulted in a dose-dependent, significant inhibition of cell growth, migration, invasiveness, and induction of apoptosis in NSCLC cells, as compared to the single agents. This was associated with a decrease in NF-κB DNA binding activity, decrease in Notch-1, Hes-1, Bcl-2 and increase in cleaved Caspase-3 and PARP expressions. These results suggest that down-regulation of Notch-1, via inhibition of NF-κB signaling pathways by Delta-Tocotrienol and cisplatin, in combination, could provide a potential novel approach for tumor arrest in NSCLC, while lowering the effective dose of cisplatin.

  • inhibition of cell growth and induction of apoptosis in non small cell lung cancer cells by delta tocotrienol is associated with notch 1 down regulation
    Journal of Cellular Biochemistry, 2011
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Smiti V. Gupta
    Abstract:

    Lung cancer is the leading cause of death among all cancers. Non-small cell lung cancer accounts for 80% of lung cancer with a 5-year survival rate of 16%. Notch pathway, especially Notch-1 is up-regulated in a subgroup of non-small cell lung cancer patients. Since Notch-1 signaling plays an important role in cell proliferation, differentiation, and apoptosis, down-regulation of Notch-1 may exert anti-tumor effects. The objective of this study was to investigate whether Delta-Tocotrienol, a naturally occurring isoform of Vitamin E, inhibits non-small cell lung cancer cell growth via Notch signaling. Treatment with Delta-Tocotrienol resulted in a dose and time dependent inhibition of cell growth, cell migration, tumor cell invasiveness, and induction of apoptosis. Real-time RT-PCR and western blot analysis showed that antitumor activity by Delta-Tocotrienol was associated with a decrease in Notch-1, Hes-1, Survivin, MMP-9, VEGF, and Bcl-XL expression. In addition, there was a decrease in NF-kB-DNA binding activity. These results suggest that down-regulation of Notch-1, via inhibition of NF-kB signaling pathways by Delta-Tocotrienol, could provide a potential novel approach for prevention of tumor progression in non-small cell lung

Zhiwei Wang - One of the best experts on this subject based on the ideXlab platform.

  • delta tocotrienol suppresses notch 1 pathway by upregulating mir 34a in nonsmall cell lung cancer cells
    International Journal of Cancer, 2012
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Arvind Goja, Smiti V. Gupta
    Abstract:

    MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating various cellular functions by transcriptional silencing. miRNAs can function as either oncogenes or tumor suppressors (oncomirs), depending on cancer types. In our study, using miRNA microarray, we observed that downregulation of the Notch-1 pathway, by Delta-Tocotrienol, correlated with upregulation of miR-34a, in nonsmall cell lung cancer cells (NSCLC). Moreover, re-expression of miR-34a by transfection in NSCLC cells resulted in inhibition of cell growth and invasiveness, induction of apoptosis and enhanced p53 activity. Furthermore, cellular mechanism studies revealed that induction of miR-34a decreased the expression of Notch-1 and its downstream targets including Hes-1, Cyclin D1, Survivin and Bcl-2. Our findings suggest that Delta-Tocotrienol is a nontoxic activator of mir-34a which can inhibit NSCLC cell proliferation, induce apoptosis and inhibit invasion, and thus offering a potential starting point for the design of novel anticancer agents.

  • Delta‐tocotrienol suppresses Notch‐1 pathway by upregulating miR‐34a in nonsmall cell lung cancer cells
    International journal of cancer, 2012
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Arvind Goja, Smiti V. Gupta
    Abstract:

    MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating various cellular functions by transcriptional silencing. miRNAs can function as either oncogenes or tumor suppressors (oncomirs), depending on cancer types. In our study, using miRNA microarray, we observed that downregulation of the Notch-1 pathway, by Delta-Tocotrienol, correlated with upregulation of miR-34a, in nonsmall cell lung cancer cells (NSCLC). Moreover, re-expression of miR-34a by transfection in NSCLC cells resulted in inhibition of cell growth and invasiveness, induction of apoptosis and enhanced p53 activity. Furthermore, cellular mechanism studies revealed that induction of miR-34a decreased the expression of Notch-1 and its downstream targets including Hes-1, Cyclin D1, Survivin and Bcl-2. Our findings suggest that Delta-Tocotrienol is a nontoxic activator of mir-34a which can inhibit NSCLC cell proliferation, induce apoptosis and inhibit invasion, and thus offering a potential starting point for the design of novel anticancer agents.

  • Delta-Tocotrienol augments cisplatin-induced suppression of non-small cell lung cancer cells via inhibition of the Notch-1 pathway
    Anticancer research, 2012
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Smiti V. Gupta
    Abstract:

    Non-small cell lung cancer (NSCLC), accounting for 80% of lung cancers, is the leading cause of all cancer deaths. Previously, we demonstrated that Delta-Tocotrienol inhibits NSCLC cell proliferation, invasion and induces apoptosis by down-regulation of the Notch-1 signaling pathway. The objective of this study was to investigate whether Delta-Tocotrienol, could enhance the anticancer effects of cisplatin. Treatment with a combination of Delta-Tocotrienol and cisplatin resulted in a dose-dependent, significant inhibition of cell growth, migration, invasiveness, and induction of apoptosis in NSCLC cells, as compared to the single agents. This was associated with a decrease in NF-κB DNA binding activity, decrease in Notch-1, Hes-1, Bcl-2 and increase in cleaved Caspase-3 and PARP expressions. These results suggest that down-regulation of Notch-1, via inhibition of NF-κB signaling pathways by Delta-Tocotrienol and cisplatin, in combination, could provide a potential novel approach for tumor arrest in NSCLC, while lowering the effective dose of cisplatin.

  • inhibition of cell growth and induction of apoptosis in non small cell lung cancer cells by delta tocotrienol is associated with notch 1 down regulation
    Journal of Cellular Biochemistry, 2011
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Smiti V. Gupta
    Abstract:

    Lung cancer is the leading cause of death among all cancers. Non-small cell lung cancer accounts for 80% of lung cancer with a 5-year survival rate of 16%. Notch pathway, especially Notch-1 is up-regulated in a subgroup of non-small cell lung cancer patients. Since Notch-1 signaling plays an important role in cell proliferation, differentiation, and apoptosis, down-regulation of Notch-1 may exert anti-tumor effects. The objective of this study was to investigate whether Delta-Tocotrienol, a naturally occurring isoform of Vitamin E, inhibits non-small cell lung cancer cell growth via Notch signaling. Treatment with Delta-Tocotrienol resulted in a dose and time dependent inhibition of cell growth, cell migration, tumor cell invasiveness, and induction of apoptosis. Real-time RT-PCR and western blot analysis showed that antitumor activity by Delta-Tocotrienol was associated with a decrease in Notch-1, Hes-1, Survivin, MMP-9, VEGF, and Bcl-XL expression. In addition, there was a decrease in NF-kB-DNA binding activity. These results suggest that down-regulation of Notch-1, via inhibition of NF-kB signaling pathways by Delta-Tocotrienol, could provide a potential novel approach for prevention of tumor progression in non-small cell lung

Mokenge P. Malafa - One of the best experts on this subject based on the ideXlab platform.

  • Chemoprevention of Azoxymethane-induced Colon Carcinogenesis by Delta-Tocotrienol
    Cancer prevention research (Philadelphia Pa.), 2019
    Co-Authors: Kazim Husain, Domenico Coppola, Chung S. Yang, Anying Zhang, Steven C Shivers, Ashley H. Davis-yadley, Mokenge P. Malafa
    Abstract:

    This study evaluated the preclinical activity of δ-tocotrienol (DT3), a bioactive form of vitamin E, in the inhibition of colorectal cancer growth and development in vitro and in vivo DT3 is the most bioactive isomer of vitamin E in inhibiting growth of colorectal cancer cells. However, it had little effect on the proliferation of normal colon mucosal cells NCM460. In HCT-116 and SW-620 colorectal cancer cells, DT3 (50 μmol/L) significantly inhibited malignant transformation (P < 0.02, P < 0.001), cell migration (P < 0.02, P < 0.05), and invasion (P < 0.05, P < 0.01) compared with vehicle. DT3 inhibited markers for epithelial (E-cadherin) to mesenchymal (vimentin) transition, metastasis (matrix metalloproteinase 9), angiogenesis VEGF, inflammation (NF-κB), and Wnt signaling (β-catenin) compared with vehicle in colorectal cancer cells. DT3 induced apoptosis selectively in colorectal cancer cells (SW-620 cells, HCT-116 cells, and HT-29) without affecting the normal colon cells. In the azoxymethane-induced colorectal carcinogenesis model in rats, DT3 (200 mg/kg orally twice a day) for 20 weeks significantly inhibited colorectal polyps by 70% and colorectal cancer by almost 99% compared with the vehicle treatment group (P < 0.02, P < 0.001), and the cancer inhibition effect was more potent than sulindac (50%). Taken together, these data demonstrate that DT3 is a potential chemopreventive agent in colorectal cancer, warranting further investigation into its clinical use in the prevention and treatment of colorectal cancer.

  • Abstract 1098: Delta-Tocotrienol chemosensitizes human pancreatic tumor metastasis to gemcitabine targeting cancer stem cells
    Experimental and Molecular Therapeutics, 2017
    Co-Authors: Kazim Husain, Said M. Sebti, Mokenge P. Malafa
    Abstract:

    Background: Pancreatic cancer, a lethal malignancy is the fourth leading cause of cancer-related deaths in the United States. The standard chemotherapy with gemcitabine is ineffective in patients with metastatic tumors. Pancreatic cancer stem cells (CSCs) have been implicated in the development of pancreatic cancer metastasis, resistance to chemotherapy and its recurrence following surgical extirpation. We have shown that natural vitamin E δ-tocotrienol is the most bioactive tocotrienols against pancreatic cancer in vitro as well as in vivo models. The purpose of this study was to evaluate the chemosensitization of pancreatic tumor metastasis by δ-tocotrienol to gemcitabine in vitro as well as in vivo. Methods: In vitro human metastatic pancreatic cancer cells L3.6pl and pancreatic cancer stem cells (PCSC) were treated with gemcitabine (5 μM) and δ-tocotrienol (50 μM) alone and in combination. Treated cells used for epithelial to mesenchymal transition (EMT), migration/invasion, microsphere/spheroid, and signaling markers assays. PCSC expressing luciferase was orthotopically implanted into pancreas of Athymic nude mice (n = 20) and after one week they were randomized into four groups: 1) vehicle control (ethanol extracted olive oil), 2) gemcitabine (100 mg/kg, IP, twice a week), 3) δ-tocotrienol (200 mg/kg, orally twice a day) and 4) gemcitabine + δ-tocotrienol. The treatment was continued for 4 weeks. The tumor volume, tumor weight, metastasis were recorded. Results: Gemcitabine slightly inhibited the growth, migration/invasion of L3.6pl and PCSC in vitro and PCSC tumor growth (tumor volume and weight) in vivo. δ-tocotrienol significantly inhibited the growth, microsphere/spheroid, migration/invasion, EMT(E-cadherin to vimentin), angiogenesis (VEGF), PCSC transcription factors (Nanog, Oct4, and Sox2), tumor growth and liver/lung metastasis compared to control. The combination of both drugs synergistically inhibited the cancer and stem cell growth, EMT, migration/invasion, microsphere/spheroid, metastasis, angiogenesis, and PCSC transcription factors in vitro as well as in vivo. Conclusion: Vitamin E δ-tocotrienol chemosensitizes human pancreatic tumor metastasis to gemcitabine through inhibition of EMT, migration, invasion, angiogenesis, cancer stem cell self-renewal, tumor growth and metastasis. Citation Format: Kazim Husain, Said M. Sebti, Mokenge P. Malafa. Delta-Tocotrienol chemosensitizes human pancreatic tumor metastasis to gemcitabine targeting cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1098. doi:10.1158/1538-7445.AM2017-1098

  • Abstract 3839: Vitamin E Delta-Tocotrienol targets human colon cancer stem cells and inhibits colon cancer metastasis and induces apoptosis
    Experimental and Molecular Therapeutics, 2016
    Co-Authors: Kazim Husain, Domenico Coppola, Said M. Sebti, Mokenge P. Malafa
    Abstract:

    Background: Colon cancer is the most commonly diagnosed cancer both in men and women and cause of cancer related deaths worldwide. Treatment for the recurrent and metastatic colon cancer remains a center of clinical attention. Cancer stem cells (CSCs) are suggested to be the only cells within tumor with tumorigenic capacity and implicated in metastasis. We have shown that vitamin E Delta-Tocotrienol (VEDT) is the most bioactive tocotrienols against cancers. This study aimed to evaluate the effect of VEDT on colon cancer growth, metastatic epithelial to mesenchymal transition (EMT), migration/ invasion/angiogenesis and colon CSCs growth and apoptosis. Methods: Human colon cancer cells HCT-116 and metastatic colon cancer cells SW-620 and colon CSCs were treated with VEDT (10-100 μM) for 72 h and cell viability recorded. VEDT (50 μM) was used for malignant transformation; migration/invasion, CSCs spheroid formation, and pluripotency were determined. Azoxymethane treated Fisher 344 rats were used as colon carcinogenesis model. They were treated with 1) vehicle control and 2) VEDT (200 mg/kg, orally twice a day) for 20 weeks. After 20 weeks the polyps and tumor formation were recorded. Results: VEDT significantly inhibited the anchorage-dependent and independent cancer cell growth, migration/invasion and induced apoptosis compared to control. VEDT inhibited the CSC spheroid formation EMT (E-cadherin to vimentin), metastasis (MMP9), angiogenesis (VEGF), CSCs transcription factors (Nanog, Oct4, Sox2 and KLF4) compared to control. Conclusion: Vitamin E Delta-Tocotrienol inhibited colon cancer growth and metastasis through inhibition of cancer stem cell pluripotency, EMT, migration, invasion, angiogenesis and induction of apoptosis. Citation Format: Kazim Husain, Domenico Coppola, Said M. Sebti, Mokenge P. Malafa. Vitamin E Delta-Tocotrienol targets human colon cancer stem cells and inhibits colon cancer metastasis and induces apoptosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3839.

  • Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites
    Cancer Chemotherapy and Pharmacology, 2016
    Co-Authors: Amit Mahipal, Jason Klapman, Shivakumar Vignesh, Chung S. Yang, Anthony Neuger, Dung-tsa Chen, Mokenge P. Malafa
    Abstract:

    Purpose Vitamin E Delta-Tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects. Methods Thirty-six subjects received from 100 to 1600 mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3 + 3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC. Results No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4–9.3 and 4.7–7.3 h, maximum concentration of 795.6–3742.6 and 493.3–3746 ng/mL, half-life of 1.7–5.9 and 2.3–6.9 h, and 0–12 h area under the curve of 4518.7–20,781.4 and 1987.7–22,171.2 ng h/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, δ-carboxyethyl hydroxychroman, and δ-carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30–60 times significantly higher than δ-tocotrienol levels. VEDT can be safely administered at doses up to 1600 mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed. Conclusions Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.

  • Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites
    Cancer chemotherapy and pharmacology, 2016
    Co-Authors: Amit Mahipal, Jason Klapman, Shivakumar Vignesh, Chung S. Yang, Anthony Neuger, Dung-tsa Chen, Mokenge P. Malafa
    Abstract:

    Purpose Vitamin E Delta-Tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects.

Fazlul H. Sarkar - One of the best experts on this subject based on the ideXlab platform.

  • delta tocotrienol suppresses notch 1 pathway by upregulating mir 34a in nonsmall cell lung cancer cells
    International Journal of Cancer, 2012
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Arvind Goja, Smiti V. Gupta
    Abstract:

    MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating various cellular functions by transcriptional silencing. miRNAs can function as either oncogenes or tumor suppressors (oncomirs), depending on cancer types. In our study, using miRNA microarray, we observed that downregulation of the Notch-1 pathway, by Delta-Tocotrienol, correlated with upregulation of miR-34a, in nonsmall cell lung cancer cells (NSCLC). Moreover, re-expression of miR-34a by transfection in NSCLC cells resulted in inhibition of cell growth and invasiveness, induction of apoptosis and enhanced p53 activity. Furthermore, cellular mechanism studies revealed that induction of miR-34a decreased the expression of Notch-1 and its downstream targets including Hes-1, Cyclin D1, Survivin and Bcl-2. Our findings suggest that Delta-Tocotrienol is a nontoxic activator of mir-34a which can inhibit NSCLC cell proliferation, induce apoptosis and inhibit invasion, and thus offering a potential starting point for the design of novel anticancer agents.

  • Delta‐tocotrienol suppresses Notch‐1 pathway by upregulating miR‐34a in nonsmall cell lung cancer cells
    International journal of cancer, 2012
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Arvind Goja, Smiti V. Gupta
    Abstract:

    MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating various cellular functions by transcriptional silencing. miRNAs can function as either oncogenes or tumor suppressors (oncomirs), depending on cancer types. In our study, using miRNA microarray, we observed that downregulation of the Notch-1 pathway, by Delta-Tocotrienol, correlated with upregulation of miR-34a, in nonsmall cell lung cancer cells (NSCLC). Moreover, re-expression of miR-34a by transfection in NSCLC cells resulted in inhibition of cell growth and invasiveness, induction of apoptosis and enhanced p53 activity. Furthermore, cellular mechanism studies revealed that induction of miR-34a decreased the expression of Notch-1 and its downstream targets including Hes-1, Cyclin D1, Survivin and Bcl-2. Our findings suggest that Delta-Tocotrienol is a nontoxic activator of mir-34a which can inhibit NSCLC cell proliferation, induce apoptosis and inhibit invasion, and thus offering a potential starting point for the design of novel anticancer agents.

  • Delta-Tocotrienol augments cisplatin-induced suppression of non-small cell lung cancer cells via inhibition of the Notch-1 pathway
    Anticancer research, 2012
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Smiti V. Gupta
    Abstract:

    Non-small cell lung cancer (NSCLC), accounting for 80% of lung cancers, is the leading cause of all cancer deaths. Previously, we demonstrated that Delta-Tocotrienol inhibits NSCLC cell proliferation, invasion and induces apoptosis by down-regulation of the Notch-1 signaling pathway. The objective of this study was to investigate whether Delta-Tocotrienol, could enhance the anticancer effects of cisplatin. Treatment with a combination of Delta-Tocotrienol and cisplatin resulted in a dose-dependent, significant inhibition of cell growth, migration, invasiveness, and induction of apoptosis in NSCLC cells, as compared to the single agents. This was associated with a decrease in NF-κB DNA binding activity, decrease in Notch-1, Hes-1, Bcl-2 and increase in cleaved Caspase-3 and PARP expressions. These results suggest that down-regulation of Notch-1, via inhibition of NF-κB signaling pathways by Delta-Tocotrienol and cisplatin, in combination, could provide a potential novel approach for tumor arrest in NSCLC, while lowering the effective dose of cisplatin.

  • inhibition of cell growth and induction of apoptosis in non small cell lung cancer cells by delta tocotrienol is associated with notch 1 down regulation
    Journal of Cellular Biochemistry, 2011
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Smiti V. Gupta
    Abstract:

    Lung cancer is the leading cause of death among all cancers. Non-small cell lung cancer accounts for 80% of lung cancer with a 5-year survival rate of 16%. Notch pathway, especially Notch-1 is up-regulated in a subgroup of non-small cell lung cancer patients. Since Notch-1 signaling plays an important role in cell proliferation, differentiation, and apoptosis, down-regulation of Notch-1 may exert anti-tumor effects. The objective of this study was to investigate whether Delta-Tocotrienol, a naturally occurring isoform of Vitamin E, inhibits non-small cell lung cancer cell growth via Notch signaling. Treatment with Delta-Tocotrienol resulted in a dose and time dependent inhibition of cell growth, cell migration, tumor cell invasiveness, and induction of apoptosis. Real-time RT-PCR and western blot analysis showed that antitumor activity by Delta-Tocotrienol was associated with a decrease in Notch-1, Hes-1, Survivin, MMP-9, VEGF, and Bcl-XL expression. In addition, there was a decrease in NF-kB-DNA binding activity. These results suggest that down-regulation of Notch-1, via inhibition of NF-kB signaling pathways by Delta-Tocotrienol, could provide a potential novel approach for prevention of tumor progression in non-small cell lung

Andreea Geamanu - One of the best experts on this subject based on the ideXlab platform.

  • delta tocotrienol suppresses notch 1 pathway by upregulating mir 34a in nonsmall cell lung cancer cells
    International Journal of Cancer, 2012
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Arvind Goja, Smiti V. Gupta
    Abstract:

    MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating various cellular functions by transcriptional silencing. miRNAs can function as either oncogenes or tumor suppressors (oncomirs), depending on cancer types. In our study, using miRNA microarray, we observed that downregulation of the Notch-1 pathway, by Delta-Tocotrienol, correlated with upregulation of miR-34a, in nonsmall cell lung cancer cells (NSCLC). Moreover, re-expression of miR-34a by transfection in NSCLC cells resulted in inhibition of cell growth and invasiveness, induction of apoptosis and enhanced p53 activity. Furthermore, cellular mechanism studies revealed that induction of miR-34a decreased the expression of Notch-1 and its downstream targets including Hes-1, Cyclin D1, Survivin and Bcl-2. Our findings suggest that Delta-Tocotrienol is a nontoxic activator of mir-34a which can inhibit NSCLC cell proliferation, induce apoptosis and inhibit invasion, and thus offering a potential starting point for the design of novel anticancer agents.

  • Delta‐tocotrienol suppresses Notch‐1 pathway by upregulating miR‐34a in nonsmall cell lung cancer cells
    International journal of cancer, 2012
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Arvind Goja, Smiti V. Gupta
    Abstract:

    MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating various cellular functions by transcriptional silencing. miRNAs can function as either oncogenes or tumor suppressors (oncomirs), depending on cancer types. In our study, using miRNA microarray, we observed that downregulation of the Notch-1 pathway, by Delta-Tocotrienol, correlated with upregulation of miR-34a, in nonsmall cell lung cancer cells (NSCLC). Moreover, re-expression of miR-34a by transfection in NSCLC cells resulted in inhibition of cell growth and invasiveness, induction of apoptosis and enhanced p53 activity. Furthermore, cellular mechanism studies revealed that induction of miR-34a decreased the expression of Notch-1 and its downstream targets including Hes-1, Cyclin D1, Survivin and Bcl-2. Our findings suggest that Delta-Tocotrienol is a nontoxic activator of mir-34a which can inhibit NSCLC cell proliferation, induce apoptosis and inhibit invasion, and thus offering a potential starting point for the design of novel anticancer agents.

  • inhibition of cell growth and induction of apoptosis in non small cell lung cancer cells by delta tocotrienol is associated with notch 1 down regulation
    Journal of Cellular Biochemistry, 2011
    Co-Authors: Zhiwei Wang, Fazlul H. Sarkar, Andreea Geamanu, Smiti V. Gupta
    Abstract:

    Lung cancer is the leading cause of death among all cancers. Non-small cell lung cancer accounts for 80% of lung cancer with a 5-year survival rate of 16%. Notch pathway, especially Notch-1 is up-regulated in a subgroup of non-small cell lung cancer patients. Since Notch-1 signaling plays an important role in cell proliferation, differentiation, and apoptosis, down-regulation of Notch-1 may exert anti-tumor effects. The objective of this study was to investigate whether Delta-Tocotrienol, a naturally occurring isoform of Vitamin E, inhibits non-small cell lung cancer cell growth via Notch signaling. Treatment with Delta-Tocotrienol resulted in a dose and time dependent inhibition of cell growth, cell migration, tumor cell invasiveness, and induction of apoptosis. Real-time RT-PCR and western blot analysis showed that antitumor activity by Delta-Tocotrienol was associated with a decrease in Notch-1, Hes-1, Survivin, MMP-9, VEGF, and Bcl-XL expression. In addition, there was a decrease in NF-kB-DNA binding activity. These results suggest that down-regulation of Notch-1, via inhibition of NF-kB signaling pathways by Delta-Tocotrienol, could provide a potential novel approach for prevention of tumor progression in non-small cell lung