Complementary Nucleobase Interactions Drive Co-Assembly of Drugs and Nanocarriers for Selective Cancer Chemotherapy

A new concept in cooperative adenine–uracil (A–U) hydrogen bonding interactions between anticancer drugs and nanocarrier complexes was successfully demonstrated by invoking the co-assembly of water soluble, uracil end-capped polyethylene glycol polymer (BU-PEG) upon association with the hydrophobic drug adenine-modified rhodamine (A-R6G). This concept holds promise as a smart and versatile drug delivery system for the achievement of targeted, more efficient cancer chemotherapy. Due to A–U base pairing between BU-PEG and A-R6G, BU-PEG has high tendency to interact with A-R6G, which leads to the formation of self-assembled A-R6G/BU-PEG nanogels in aqueous solution. The resulting nanogels exhibit a number of unique physical properties, including extremely high A-R6G-loading capacity, well-controlled, pH-triggered A-R6G release behavior, and excellent structural stability in biological media. Importantly, a series of in vitro cellular experiments clearly demonstrated that A-R6G/BU-PEG nanogels improved the selective uptake of A-R6G by cancer cells via endocytosis and promoted the intracellular release of A-R6G to subsequently induce apoptotic cell death, while control rhodamine/BU-PEG nanogels did not exert selective toxicity in cancer or normal cell lines. Overall, these results indicate that cooperative A–U base pairing within nanogels is a critical factor that improves selective drug uptake and effectively promotes apoptotic programmed cell death in cancer cells.

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The effect of continuous combined 17β-oestradiol and dihydrodydrogesterone on apoptotic cell death and proliferation of human breast cancer cells in vitro

European Journal of Cancer ◽

10.1016/s0959-8049(02)00293-9 ◽

2002 ◽

Vol 38 ◽

pp. 69-70 ◽

Cited By ~ 6

Author(s):

H.R Franke ◽

I Vermes

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Human Breast Cancer Cells ◽

Human Breast

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Fisetin mediated apoptotic cell death in parental and Oxaliplatin/irinotecan resistant colorectal cancer cells in vitro and in vivo

Journal of Cellular Physiology ◽

10.1002/jcp.26532 ◽

2018 ◽

Vol 233 (9) ◽

pp. 7134-7142 ◽

Cited By ~ 16

Author(s):

Long-Bin Jeng ◽

Bharath Kumar Velmurugan ◽

Ming-Cheng Chen ◽

Hsi-Hsien Hsu ◽

Tsung-Jung Ho ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Death ◽

Cancer Cells ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Colorectal Cancer Cells

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A Potential Antineoplastic Peptide of Human Prostate Cancer Cells Derived from the Lesser Spotted Dogfish (Scyliorhinus canicula L.)

Marine Drugs ◽

10.3390/md17100585 ◽

2019 ◽

Vol 17 (10) ◽

pp. 585 ◽

Cited By ~ 1

Author(s):

Adrien Bosseboeuf ◽

Amandine Baron ◽

Elise Duval ◽

Aude Gautier ◽

Pascal Sourdaine ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Cell Death ◽

Growth Inhibition ◽

Cancer Cells ◽

Apoptotic Cell ◽

Prostate Cancer Cells ◽

Cell Death Mechanisms ◽

Autophagy Inhibition

The purpose of the present paper is to investigate the mechanism of action of a pyroglutamate-modified peptide (pE-K092D) on in vitro growth inhibition of MDA-Pca-2b prostate cancer cells. This peptide was derived from a peptide previously isolated from the testis of the lesser spotted dogfish and identified as QLTPEALADEEEMNALAAR (K092D). The effect of the peptide on cell proliferation and cell death mechanisms was studied by flow cytometry. Cellular morphology and cytoskeleton integrity of peptide-treated cells were observed by immunofluorescence microscopy. Results showed the onset of peptide induced early cytoskeleton perturbation, inhibition of autophagy, inhibition of cell proliferation and, at the end, non-apoptotic cell death mechanisms (membrane destabilization and necrosis). All those mechanisms seem to contribute to MDA-Pca-2b growth inhibition by a main cytostatic fate.

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Apoptotic cell death: A possible key event in mediating the in vitro anti-proliferative effect of a novel copper(II) complex, [Cu(4-Mecdoa)(phen)2] (phen=phenanthroline, 4-Mecdoa=4-methylcoumarin-6,7-dioxactetate), in human malignant cancer cells

European Journal of Pharmacology ◽

10.1016/j.ejphar.2007.04.064 ◽

2007 ◽

Vol 569 (1-2) ◽

pp. 16-28 ◽

Cited By ~ 29

Author(s):

Bhumika Thati ◽

Andy Noble ◽

Bernadette S. Creaven ◽

Maureen Walsh ◽

Kevin Kavanagh ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Proliferative Effect

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Electrochemotherapy Causes Caspase-Independent Necrotic-Like Death in Pancreatic Cancer Cells

Cancers ◽

10.3390/cancers11081177 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1177 ◽

Cited By ~ 3

Author(s):

Philana Fernandes ◽

Tracey R. O’Donovan ◽

Sharon L. McKenna ◽

Patrick F. Forde

Keyword(s):

Pancreatic Cancer ◽

Cell Death ◽

Cancer Cells ◽

Patient Survival ◽

Morphological Changes ◽

Drug Uptake ◽

Cancer Therapies ◽

Pancreatic Cancer Cells ◽

Membrane Porosity

Pancreatic cancer represents a major challenge in oncology. Poor permeability of the pancreas and resistance to currently available therapies are impediments to improved patient survival. By transiently increasing cell membrane porosity and increasing drug uptake, Electrochemotherapy (ECT) has the potential to overcome these issues. In this study, we have evaluated the response of human and murine pancreatic cancer cells, in vitro, to electroporation in combination with Bleomycin, Cisplatin, or Oxaliplatin (ECT). The cytotoxic actions of all three drugs are potentiated when combined with electroporation in these cells. The biochemical and morphological changes post ECT are associated with immunogenic cell death that occurs with necroptosis rather than apoptosis. Moreover, ECT-induced cell death is rescued by Nec-1 suggesting that necroptosis may play a role in cell death mediated by cancer therapies.

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Lignan enriched fraction (LRF) of Phyllanthus amarus promotes apoptotic cell death in human cervical cancer cells in vitro

Scientific Reports ◽

10.1038/s41598-019-51480-7 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Subhabrata Paul ◽

Debashis Patra ◽

Rita Kundu

Keyword(s):

Cervical Cancer ◽

Cell Death ◽

Cancer Cells ◽

Apoptotic Cell ◽

Growth Substance ◽

Apoptotic Cell Death ◽

Chloroform Fraction ◽

Phyllanthus Amarus ◽

Cervical Cancer Cells

Abstract Phyllanthus amarus is widely grown in this sub-continent and used traditionally to treat many common ailments. In the present study, lignan rich fraction of P. amarus extract was used on cervical cancer cell lines (HeLa, SiHa and C33A) to study it’s mechanism of cell death induction. As the cells were treated with IC50 doses of LRF, characteristic apoptotic features were observed. Increased sub G0 population were observed both in Hela and C33 cells, while G1/S arrest was observed in SiHa cells than their untreated counterparts. Increased production of ROS and change in MMP were also detected in the treated cells. Presence of γH2AX, was observed by immunofluorescence. Reduced expression of HPV (16/18) as well as ET-1, an autocrine growth substance, were observed in the treated cells. Immunoblotting as well as ICFC studies showed enhanced expressions of BAX, Caspase 3 and PARP (cleaved) in the treated cells. A major lignan, phyllanthin was isolated from the chloroform fraction and showed strong irreversible affinities for viral E6 and MDM2 in in silico analysis. The study conclusively indicates that LRF has the potential to induce apoptotic cell death in cervical cancer cells by activation of p53 and p21 against DNA damage.

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Inhibition of cathepsin K sensitizes oxaliplatin-induced apoptotic cell death by Bax upregulation through OTUB1-mediated p53 stabilization in vitro and in vivo

Oncogene ◽

10.1038/s41388-021-02088-7 ◽

2021 ◽

Author(s):

Seung Un Seo ◽

Seon Min Woo ◽

Shin Kim ◽

Jong-Wook Park ◽

Hyun-Shik Lee ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Apoptotic Cell ◽

Critical Role ◽

Cathepsin K ◽

Apoptotic Cell Death ◽

Mouse Xenograft Model ◽

Induced Apoptosis ◽

Cathepsin K Inhibition

AbstractCathepsin K is highly expressed in various types of cancers. However, the effect of cathepsin K inhibition in cancer cells is not well characterized. Here, cathepsin K inhibitor (odanacatib; ODN) and knockdown of cathepsin K (siRNA) enhanced oxaliplatin-induced apoptosis in multiple cancer cells through Bax upregulation. Bax knockdown significantly inhibited the combined ODN and oxaliplatin treatment-induced apoptotic cell death. Stabilization of p53 by ODN played a critical role in upregulating Bax expression at the transcriptional level. Casein kinase 2 (CK2)-dependent phosphorylation of OTUB1 at Ser16 played a critical role in ODN- and cathepsin K siRNA-mediated p53 stabilization. Interestingly, ODN-induced p53 and Bax upregulation were modulated by the production of mitochondrial reactive oxygen species (ROS). Mitochondrial ROS scavengers prevented OTUB1-mediated p53 stabilization and Bax upregulation by ODN. These in vitro results were confirmed by in mouse xenograft model, combined treatment with ODN and oxaliplatin significantly reduced tumor size and induced Bax upregulation. Furthermore, human renal clear carcinoma (RCC) tissues revealed a strong correlation between phosphorylation of OTUB1(Ser16) and p53/Bax expression. Our results demonstrate that cathepsin K inhibition enhances oxaliplatin-induced apoptosis by increasing OTUB1 phosphorylation via CK2 activation, thereby promoting p53 stabilization, and hence upregulating Bax.

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