Mayank Thakur - Academia.edu (original) (raw)

Papers by Mayank Thakur

<b>Copyright information:</b>Taken from "Immunomodulatory Activity of Sant. F&qu... more <b>Copyright information:</b>Taken from "Immunomodulatory Activity of Sant. F"Evidence-based Complementary and Alternative Medicine : eCAM 2006;4(4):419-423.Published online 13 Dec 2006PMCID:PMC2176149.© 2006 The Author(s). & F. on azathioprine induced suppression of hematological parameters.

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Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an 1 anti-calcitonin ... more Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an 1 anti-calcitonin receptor antibody, are differentially potent in vitro in high grade 2 glioma cell lines derived from glioblastoma 3 4 Roger Gilabert-Oriol, Sebastian G.B. Furness, Brett W. Stringer, Alexander Weng, 5 Hendrik Fuchs, Bryan W. Day, Angela Kourakis, Andrew W. Boyd, David L. Hare, 6 Mayank Thakur, Terrance G. Johns, Peter J. Wookey. 7

Planta Medica, 2019

The ability of certain triterpenoid saponins to modulate the endosomal release during the process... more The ability of certain triterpenoid saponins to modulate the endosomal release during the process of endocytosis and to ensure a nontoxic and efficient transfection recently led to an exceptional interest in the field of nonviral gene delivery. In vitro and in vivo studies demonstrated promising results in terms of tumor growth inhibition after the delivery of a suicide gene such as saporin and dianthin. With that, the question arises which structural features are necessary or advantageous to achieve an effective endosomal escape. Former studies described certain important characteristics a potent saponin should have. Particularly SA1641 (Gypsophila paniculata) and SO1861 (Saponaria officinalis) played an utmost important role to get a first insight into the structure-activity relationship. However, a number of issues such as the purpose of functional groups on the aglycon and the substitution of sugars and their modification remain unsolved and their value needs to be specified. By...

Cancer immunology, immunotherapy : CII, Jan 13, 2017

We have reported that calcitonin receptor (CTR) is widely expressed in biopsies from the lethal b... more We have reported that calcitonin receptor (CTR) is widely expressed in biopsies from the lethal brain tumour glioblastoma by malignant glioma and brain tumour-initiating cells (glioma stem cells) using anti-human CTR antibodies. A monoclonal antibody against an epitope within the extracellular domain of CTR was raised (mAb2C4) and chemically conjugated to either plant ribosome-inactivating proteins (RIPs) dianthin-30 or gelonin, or the drug monomethyl auristatin E (MMAE), and purified. In the high-grade glioma cell line (HGG, representing glioma stem cells) SB2b, in the presence of the triterpene glycoside SO1861, the EC50 for mAb2C4:dianthin was 10.0 pM and for mAb2C4:MMAE [antibody drug conjugate (ADC)] 2.5 nM, 250-fold less potent. With the cell line U87MG, in the presence of SO1861, the EC50 for mAb2C4:dianthin was 20 pM, mAb2C4:gelonin, 20 pM, compared to the ADC (6.3 nM), which is >300 less potent. Several other HGG cell lines that express CTR were tested and the efficacies...

Planta Medica, 2016

Triterpenoidal saponins are synthesized in the roots of Saponaria officinalis L. The same plant i... more Triterpenoidal saponins are synthesized in the roots of Saponaria officinalis L. The same plant is also a source for the toxin Saporin, which is a ribosome-inactivating protein. Triterpenoidal saponins are known to increase the cytotoxicity of Saporin by modulating its intracellular trafficking. Here, we investigated if the combinatorial effects elicited by purified saponins and Saporin can be applied to increase the therapeutic efficacy of the immunotoxin Saporin-Rituximab. First, saponins were purified by high-performance liquid chromatography. Thereafter, their intrinsic cytotoxicity was evaluated on Ramos cells with no observed effect up to 5 µg/mL, however, saponins increased the cytotoxicity of Saporin, while no influence was observed on its N-glycosidase activity. Saporin-Rituximab bound to CD20 in Ramos cells and, in the absence of saponins, had a GI50 (concentration inhibiting cell growth to 50 %) of 7 nM. However, in the presence of a nontoxic concentration of saponins, the GI50 of Saporin-Rituximab was 0.01 nM, a nearly 700-fold increase in efficacy. Moreover, two further immunotoxins, namely Saporin-anti-CD22 and Saporin-anti-CD25, were tested in combination with saponins yielding enhancement factors of 170-fold and 25-fold, respectively. All three receptors are present in Ramos cells and the differences in cytotoxicity enhancement may be explained by the differing expression levels of the cellular receptors. The application of purified saponins from S. officinalis L. is therefore a new strategy to potentially improve the cytotoxicity and therapeutic efficacy of Rituximab-immunotoxins for the treatment of B-cell lymphoma.

Letters in Drug Design Amp Discovery, 2015

Molecular Cancer Therapeutics, 2013

Antitumor therapy with monoclonal antibodies has shown great therapeutic benefits in clinics and ... more Antitumor therapy with monoclonal antibodies has shown great therapeutic benefits in clinics and a number of therapeutic antibodies have been approved for use in patients. Nevertheless, their efficacy is limited due to their insufficient inherent cell killing activity. In order to augment their antitumor efficacy, monoclonal antibodies may be modified with natural toxins to create a drug conjugate (immunotoxin) that comprises the dual functionality of monoclonal antibody (antagonistic binding to targeted receptors and interaction with the innate immune system) and the cell-killing activity of the toxin. In our investigations, two immunotoxins were prepared by chemically coupling the monoclonal antibodies trastuzumab (Herceptin®) and cetuximab (Erbitux®) to the plant derived toxin saporin via a cleavable disulfide bond. Impedance-based real-time viability assays and confocal live cell imaging revealed that the toxin is efficiently delivered to the targeted tumor cells. In addition, i...

Journal of Chinese Integrative Medicine

ABSTRACT

Journal of alternative and complementary medicine (New York, N.Y.)

Botanics: Targets and Therapy, 2011

Saponins are bioactive compounds produced mainly by plants but also by some marine organisms and ... more Saponins are bioactive compounds produced mainly by plants but also by some marine organisms and insects. In the recent past, there has been unforeseen interest in the clinical utilization of saponins as chemotherapeutic agents. The research on saponins in various forms as a treatment for cancer has generated a lot of potential. The advent of nanotechnology and the cytotoxicity enhancing properties of saponins are some of the highlights of the current decade. This review gives an updated overview of the clinical potential that saponins hold as cytotoxic agents, and covers the literature for 1957-2011, with the main focus on research conducted in the last decade. It is conceivable that saponins hold a lot of therapeutic potential and could be a lead for identification of synthetic or semisynthetic molecules for the treatment of cancer via membrane-mediated or transport-mediated pathways.

Journal of Cosmetic Dermatology

Biochemical Pharmacology, 2015

The therapeutic relevance of immunotoxins is based on the conjugation of monoclonal antibodies to... more The therapeutic relevance of immunotoxins is based on the conjugation of monoclonal antibodies to toxins. In cancer therapies, the conjugated antibodies not only direct the binding of immunotoxins to cancer-specific receptors and mediate the elimination of tumor cells through the innate immune system, but also increase target cytotoxicity by the intrinsic toxin activity. In the present study, the therapeutic antibodies Cetuximab (anti-EGFR, Erbitux(®)), Panitumumab (anti-EGFR, Vectibix(®)) and Trastuzumab (anti-HER2, Herceptin(®)) were chemically conjugated to the toxin dianthin. In the first instance, recombinant dianthin was characterized by mass spectrometry and its stability was analyzed by circular dichroism. Dianthin showed increased cytotoxicity on MCF-7 cells when tested in combination with a glycosylated triterpenoid (SO1861) in a real-time impedance-based cytotoxicity assay. In data obtained by live cell imaging, SO1861 specifically mediated the endo/lysosomal escape of dianthin without disrupting the plasma membrane. The purity of immunotoxins was confirmed by SDS-PAGE and Western blot. Their cytotoxicity was evaluated in the presence of SO1861 and dianthin-Cetuximab presented a GI50 (50% growth inhibition) of 5.3pM, dianthin-Panitumumab of 1.5pM, and dianthin-Trastuzumab of 23pM. Finally, the specificity of these immunotoxins was validated in a fluorescence-based real-time assay, where their binding to target cells was prevented by preincubation with an excess of label-free unconjugated antibody. Based on these data, we propose the use of dianthin and SO1861 as a new platform technology to enhance the efficacy of therapeutic antibodies.