Sutapa Sinha

Publications (18) View all

• Article: Plumbagin inhibits tumorigenesis and angiogenesis of ovarian cancer cells in vivo.

  Sutapa Sinha, Krishnendu Pal, Ahmed Elkhanany, Shamit Dutta, Ying Cao, Gourish Mondal, Seethalakshmi Iyer, Veena Somasundaram, Fergus J Couch, Viji Shridhar, Resham Bhattacharya, Debabrata Mukhopadhyay, Priya Srinivas
  [show abstract] [hide abstract]
  ABSTRACT: Angiogenesis is a hallmark of tumor development and metastatic progression, and anti-angiogenic drugs targeting the VEGF pathway have shown to decrease the disease progression in cancer patients. In this study, we have analyzed the anti-proliferative and anti-angiogenic property of plumbagin in cisplatin sensitive, BRCA2 deficient, PEO-1 and cisplatin resistant, BRCA2 proficient PEO-4 ovarian cancer cells. Both PEO-1 and PEO-4 ovarian cancer cells are sensitive to plumbagin irrespective of BRCA2 status in both normoxia and hypoxia. Importantly, plumbagin treatment effectively inhibits VEGF-A and Glut-1 in PEO-1 and PEO-4 ovarian cancer cells. We have also analyzed the p53 mutant, cisplatin resistant, and BRCA2 proficient OVCAR-5 cells. Plumbagin challenge also restricts the VEGF induced pro-angiogenic signaling in HUVECs and subsequently endothelial cell proliferation. In addition, we observe a significant effect on tumor regression among OVCAR-5 tumor-bearing mice treated with plumbagin, which is associated with significant inhibition of Ki67 and vWF expressions. Plumbagin also significantly reduces CD31 expression in an ear angiogenesis assay. Collectively, our studies indicate that plumbagin, as an anti-cancer agent disrupts growth of ovarian cancer cells through the inhibition of proliferation as well as angiogenesis.
  International Journal of Cancer 07/2012; · 5.44 Impact Factor
• Article: Von Hippel-Lindau gene product directs cytokinesis: a new tumor suppressor function.

  Sutapa Sinha, Gourish Mondal, Eun Ju Hwang, Da Woon Han, Shamit K Dutta, Seethalakshmi Iyer, S Ananth Karumanchi, Keun Il Kim, Fergus J Couch, Debabrata Mukhopadhyay
  [show abstract] [hide abstract]
  ABSTRACT: One of the mechanisms of tumorigenesis is that the failure of cell division results in genetically unstable, multinucleated cells. Here we show that pVHL, a tumor suppressor protein that has been implicated in the pathogenesis of renal cell carcinoma (RCC), plays an important role in regulation of cytokinesis. We found that pVHL-deficient RCC 786-O cells were multinucleated and polyploid. Reintroduction of wild-type pVHL into these cells rescued the diploid cell population, whereas the mutant pVHL-K171G failed to do so. We demonstrate that lysine 171 of pVHL is important for the final step of cytokinesis: the midbody abscission. The pVHL-K171G caused failure to localize the ESCRT-1 interacting protein Alix and the v-SNARE complex component Endobrevin to the midbody in 786-O cells, leading to defective cytokinesis. Moreover, SUMOylation of pVHL at lysine 171 might modulate its function as a cytokinesis regulator. pVHL tumor suppressor function was also disrupted by the K171G mutation, as evidenced by the xenograft tumor formation when 786-O clones expressing pVHL-K171G were injected into mice. Most RCC cell lines show a polyploid chromosome complement and consistent heterogeneity in chromosome number. Thus, this study offers a way to explain the chromosome instability in RCC and reveals a new direction for the tumor suppressor function of pVHL, which is independent of its E3 ubiquitin ligase activity.
  Journal of Cell Science 07/2011; 124(Pt 13):2132-42. · 6.11 Impact Factor
• Article: Structure-activity study to develop cationic lipid-conjugated haloperidol derivatives as a new class of anticancer therapeutics.

  Krishnendu Pal, SubrataKumar Pore, Sutapa Sinha, Rajiv Janardhanan, Debabrata Mukhopadhyay, Rajkumar Banerjee
  [show abstract] [hide abstract]
  ABSTRACT: Haloperidol (HP), a neuroleptic drug, shows high affinity toward σ receptors (SR). HP and reduced-HP at higher concentration were known to induce apoptosis in SR-overexpressing carcinomas and melanomas. Herein, we report the development of cationic lipid-conjugated haloperidol as a new class of anticancer therapeutics. In comparison to HP, the C-8 carbon chain analogue (HP-C8) showed significantly high, SR-assisted antiproliferative activity against cancer cells via caspase-3-mediated apoptosis and down-regulation of pAkt. Moreover, melanoma tumor aggressiveness in HP-C8-treated mice was significantly lower than that in HP-treated mice. HP-C8 simultaneously reduced Akt-protein level and increased Bax/Bcl-2 ratio in vascular endothelial cells, thereby indicating a possible protein kinase down-regulatory and apoptosis inducing role in tumor-associated vascular cells. In conclusion, we developed σ receptor-targeting cationic lipid-modified HP derivatives as a promising class of anticancer therapeutic that concurrently affects cancer and tumor environment associated angiogenic vascular cells through induction of apoptosis and Akt protein down-regulation.
  Journal of Medicinal Chemistry 03/2011; 54(7):2378-90. · 4.80 Impact Factor
• Source

  Available from: Rajkumar Banerjee

  Article: A lipid-modified estrogen derivative that treats breast cancer independent of estrogen receptor expression through simultaneous induction of autophagy and apoptosis.

  Sutapa Sinha, Sayantani Roy, Bathula Surendar Reddy, Krishnendu Pal, Godeshala Sudhakar, Seethalakshmi Iyer, Shamit Dutta, Enfeng Wang, Pawan Kumar Vohra, Karnati Rammohan Roy, Pallu Reddanna, Debabrata Mukhopadhyay, Rajkumar Banerjee
  [show abstract] [hide abstract]
  ABSTRACT: It is a challenge to develop a universal single drug that can treat breast cancer at single- or multiple-stage complications, yet remains nontoxic to normal cells. The challenge is even greater when breast cancer-specific, estrogen-based drugs are being developed that cannot act against multistaged breast cancer complications owing to the cells differential estrogen receptor (ER) expression status and their possession of drug-resistant and metastatic phenotypes. We report here the development of a first cationic lipid-conjugated estrogenic derivative (ESC8) that kills breast cancer cells independent of their ER expression status. This ESC8 molecule apparently is nontoxic to normal breast epithelial cells, as well as to other noncancer cells. ESC8 induces apoptosis through an intrinsic pathway in ER-negative MDA-MB-231 cells. In addition, ESC8 treatment induces autophagy in these cells by interfering with the mTOR activity. This is the first example of an estrogen structure-based molecule that coinduces apoptosis and autophagy in breast cancer cells. Further in vivo study confirms the role of this molecule in tumor regression. Together, our results open new perspective of breast cancer chemotherapy through a single agent, which could provide the therapeutic benefit across all stages of breast cancer.
  Molecular Cancer Research 02/2011; 9(3):364-74. · 4.29 Impact Factor
• Article: Ephrin B2/EphB4 pathway in hepatic stellate cells stimulates Erk-dependent VEGF production and sinusoidal endothelial cell recruitment.

  Amitava Das, Uday Shergill, Lokendra Thakur, Sutapa Sinha, Raul Urrutia, Debabrata Mukhopadhyay, Vijay H Shah
  [show abstract] [hide abstract]
  ABSTRACT: Chemotaxis signals between hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC) maintain hepatic vascular homeostasis and integrity and also regulate changes in sinusoidal structure in response to liver injury. Our prior studies have demonstrated that the bidirectional chemotactic signaling molecules EphrinB2 and EphB4 are expressed in HSC. The aim of our present study was to explore whether and how the EphrinB2/EphB4 system in HSC could promote SEC recruitment, which is essential for sinusoidal structure and remodeling. Stimulation of human HSC (hHSC) with chimeric agonists (2 microg/ml) of either EphrinB2 or EphB4 (EphrinB2 Fc or EphB4 Fc, respectively) significantly increased VEGF mRNA levels in hHSC as assessed by quantitative PCR, with respective small interfering RNAs for EphrinB2 and EphB4 inhibiting this increase (P < 0.05, n = 3). EphrinB2 agonist-induced increase in VEGF mRNA levels in hHSC was associated with increased phosphorylation of Erk and was significantly blocked by U0126 (20 microM), an inhibitor of MEK, which is a kinase upstream from Erk (P < 0.05, n = 3). The EphB4 agonist also significantly increased human VEGF promoter activity (P < 0.05, n = 3) as assessed by promoter reporter luciferase assay in transfected LX2-HSC. This was associated with upregulation of the vasculoprotective transcription factor, Kruppel-like factor 2 (KLF2). In Boyden chamber assays, conditioned media from hHSC stimulated with agonists of EphrinB2 or EphB4 increased SEC chemotaxis in a VEGF-dependent manner, compared with control groups that included basal media with agonists of EphrinB2, EphB4, or HSC-conditioned media from HSC in absence of agonist stimulation (P < 0.05, n = 3). EphB4 expression was detected in situ within liver sinusoidal vessels of rats after carbon tetrachloride-induced liver injury. In summary, activation of the EphrinB2/EphB4 signaling pathway in HSC promotes chemotaxis of SEC through a pathway that involves Erk, KLF2, and VEGF. These studies identify EphrinB2 or EphB4 as a key intermediary that links HSC signal transduction pathways with angiogenesis and sinusoidal remodeling.
  AJP Gastrointestinal and Liver Physiology 03/2010; 298(6):G908-15. · 3.43 Impact Factor