The Hsp70 inhibiting peptide aptamer A17 potentiates radiosensitization of tumor cells by Hsp90 inhibition

Abstract Tumor cells adapt their metabolism to meet the energetic and anabolic requirements of high proliferation and invasiveness. The metabolic addiction has motivated the development of therapies directed at individual biochemical nodes. However, currently there are few possibilities to target multiple enzymes in tumors simultaneously. Flavin-containing enzymes, ca. 100 proteins in humans, execute key biotransformations in mammalian cells. To expose metabolic addiction, we inactivated a substantial fraction of the flavoproteome in melanoma cells by restricting the supply of the FMN and FAD precursor riboflavin, the vitamin B2. Vitamin B2 deficiency affected stability of many polypeptides and thus resembled the chaperone HSP90 inhibition, the paradigmatic multiple-target approach. In support of this analogy, flavin-depleted proteins increasingly associated with a number of proteostasis network components, as identified by the mass spectrometry analysis of the FAD-free NQO1 aggregates. Proteome-wide analysis of the riboflavin-starved cells revealed a profound inactivation of the mevalonate pathway of cholesterol synthesis, which underlines the manifold cellular vulnerability created by the flavoproteome inactivation. Cell cycle-arrested tumor cells became highly sensitive to alkylating chemotherapy. Our data suggest that the flavoproteome is well suited to design synthetic lethality protocols combining proteostasis manipulation and metabolic reprogramming.

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Inhibition of Stat3 by peptide aptamer rS3-PA enhances growth suppressive effects of irinotecan on colorectal cancer cells

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2012-0014 ◽

2012 ◽

Vol 10 (2) ◽

Cited By ~ 1

Author(s):

Axel Weber ◽

Corina Borghouts ◽

Natalia Delis ◽

Laura Mack ◽

Boris Brill ◽

...

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Tumor Cells ◽

Cytotoxic Agents ◽

Cytotoxic Action ◽

Signal Transducer ◽

Intrinsic Resistance ◽

Colorectal Cancer Cells ◽

Peptide Aptamer

AbstractCytotoxic agents, alone or in combination, are being used in the treatment of colorectal cancer. Despite progress in the therapeutic regimes, this common malignancy is still the cause of considerable morbidity and mortality, and further improvements are required. Cancer cells often exhibit intrinsic resistance against chemotherapeutic agents or they develop resistance over the time of treatment. Several mechanisms have been made responsible, e.g., drugs may fail to reach tumor cells or drugs may fail to elicit cytotoxicity. The molecular characterization of drug resistance in cancer cells may lead to strategies to overcome it and enhance the sensitivity to chemotherapy. Irinotecan is one of the main treatments of colorectal cancer; it is converted into its active metabolite SN38 and acts as a topoisomerase I inhibitor. Inhibition of this enzyme prevents DNA relegation following uncoiling. Irinotecan has been used as a chemotherapeutic agent either as a single agent or in combination with 5-fluorouracil and targeted therapies directed against the epidermal growth factor receptor, such as cetuximab. The transcription factor signal transducer and activator of transcription 3 (Stat3) is a member of the signal transducer and activator of transcription protein family. Its persistent activation is found in tumor cells and has been associated with drug and radiation resistance. The treatment of colorectal cancer cells with irinotecan leads to senescence or apoptosis following DNA double-strand break induction. This process is impaired by the activation of Stat3. We have derived a Stat3 specific peptide aptamer [recombinant Stat3 inhibitory peptide aptamer (rS3-PA)] that recognizes the dimerization domain of Stat3 and effectively inhibits its function. The delivery of rS3-PA into colon cancer cells and the resulting inhibition of Stat3 strongly enhanced the cytotoxic action of SN38. These data show that the targeted inhibition of Stat3 decreases drug resistance and enhances SN38-mediated cell death. The combination of these agents has a potent antitumor effect and could become beneficial for the treatment of patients with colorectal cancer.

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Molecularly engineered carrier-free co-delivery nanoassembly for self-sensitized photothermal cancer therapy

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01037-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Xinzhu Shan ◽

Xuanbo Zhang ◽

Chen Wang ◽

Zhiqiang Zhao ◽

Shenwu Zhang ◽

...

Keyword(s):

Cancer Therapy ◽

Tumor Cells ◽

Xenograft Model ◽

Hsp90 Inhibitor ◽

Therapeutic Modality ◽

Gambogic Acid ◽

Hsp90 Inhibition ◽

Photothermal Conversion ◽

Synergistic Cytotoxicity ◽

Carrier Free

Abstract Background Photothermal therapy (PTT) has been extensively investigated as a tumor-localizing therapeutic modality for neoplastic disorders. However, the hyperthermia effect of PTT is greatly restricted by the thermoresistance of tumor cells. Particularly, the compensatory expression of heat shock protein 90 (HSP90) has been found to significantly accelerate the thermal tolerance of tumor cells. Thus, a combination of HSP90 inhibitor and photothermal photosensitizer is expected to significantly enhance antitumor efficacy of PTT through hyperthermia sensitization. However, it remains challenging to precisely co-deliver two or more drugs into tumors. Methods A carrier-free co-delivery nanoassembly of gambogic acid (GA, a HSP90 inhibitor) and DiR is ingeniously fabricated based on a facile and precise molecular co-assembly technique. The assembly mechanisms, photothermal conversion efficiency, laser-triggered drug release, cellular uptake, synergistic cytotoxicity of the nanoassembly are investigated in vitro. Furthermore, the pharmacokinetics, biodistribution and self-enhanced PTT efficacy were explored in vivo. Results The nanoassembly presents multiple advantages throughout the whole drug delivery process, including carrier-free fabrication with good reproducibility, high drug co-loading efficiency with convenient dose adjustment, synchronous co-delivery of DiR and GA with long systemic circulation, as well as self-tracing tumor accumulation with efficient photothermal conversion. As expected, HSP90 inhibition-augmented PTT is observed in a 4T1 tumor BALB/c mice xenograft model. Conclusion Our study provides a novel and facile dual-drug co-assembly strategy for self-sensitized cancer therapy. Graphic abstract

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A membrane penetrating peptide aptamer inhibits STAT3 function and suppresses the growth of STAT3 addicted tumor cells

JAK-STAT ◽

10.4161/jkst.18947 ◽

2012 ◽

Vol 1 (1) ◽

pp. 44-55 ◽

Cited By ~ 3

Author(s):

Corina Borghouts ◽

Natalia Delis ◽

Boris Brill ◽

Astrid Weiss ◽

Laura Mack ◽

...

Keyword(s):

Tumor Cells ◽

Peptide Aptamer

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Increased radiosensitization in cervical tumor cells following HSP90 inhibition with geldanamycin

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/s0360-3016(03)01161-1 ◽

2003 ◽

Vol 57 (2) ◽

pp. S298-S299 ◽

Cited By ~ 1

Author(s):

S.E Karimpour ◽

C Bradbury ◽

D Mattson ◽

K.S Bisht ◽

D Gius

Keyword(s):

Tumor Cells ◽

Cervical Tumor ◽

Hsp90 Inhibition

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The Inhibition of Stat5 by a Peptide Aptamer Ligand Specific for the DNA Binding Domain Prevents Target Gene Transactivation and the Growth of Breast and Prostate Tumor Cells

Pharmaceuticals ◽

10.3390/ph6080960 ◽

2013 ◽

Vol 6 (8) ◽

pp. 960-987 ◽

Cited By ~ 9

Author(s):

Axel Weber ◽

Corina Borghouts ◽

Christian Brendel ◽

Richard Moriggl ◽

Natalia Delis ◽

...

Keyword(s):

Dna Binding ◽

Tumor Cells ◽

Human Tumor ◽

Binding Domain ◽

Dna Binding Domain ◽

Protein Activity ◽

Intracellular Degradation ◽

Wide Range ◽

Peptide Aptamer ◽

Prostate Tumor Cells

The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment.

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Membranous alterations in the cytoplasm and nucleus in a primitive neuroectodermal tumor of the brain

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100084016 ◽

1978 ◽

Vol 36 (2) ◽

pp. 628-629

Author(s):

C. N. Sun ◽

C. Araoz ◽

H. J. White

Keyword(s):

Nuclear Envelope ◽

Tumor Cells ◽

Osmium Tetroxide ◽

Primitive Neuroectodermal Tumor ◽

Uranyl Acetate ◽

Neuroectodermal Tumor ◽

Annulate Lamellae ◽

Lead Citrate ◽

Thin Sections ◽

The Brain

The ultrastructure of a cerebral primitive neuroectodermal tumor has been reported previously. In the present case, we will present some unusual previously unreported membranous structures and alterations in the cytoplasm and nucleus of the tumor cells.Specimens were cut into small pieces about 1 mm3 and immediately fixed in 4% glutaraldehyde in phosphate buffer for two hours, then post-fixed in 1% buffered osmium tetroxide for one hour. After dehydration, tissues were embedded in Epon 812. Thin sections were stained with uranyl acetate and lead citrate.In the cytoplasm of the tumor cells, we found paired cisternae (Fig. 1) and annulate lamellae (Fig. 2) noting that the annulate lamellae were sometimes associated with the outer nuclear envelope (Fig. 3). These membranous structures have been reported in other tumor cells. In our case, mitochondrial to nuclear envelope fusions were often noted (Fig. 4). Although this phenomenon was reported in an oncocytoma, their frequency in the present study is quite striking.

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