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Metal-Based G-Quadruplex Binders for Cancer Theranostics.

ABSTRACT: The ability of fluorescent small molecules, such as metal complexes, to selectively recognize G-quadruplex (G4) structures has opened a route to develop new probes for the visualization of these DNA structures in cells. The main goal of this review is to update the most recent research efforts towards the development of novel cancer theranostic agents using this type of metal-based probes that specifically recognize G4 structures. This encompassed a comprehensive overview of the most significant progress in the field, namely based on complexes with Cu, Pt, and Ru that are among the most studied metals to obtain this class of molecules. It is also discussed the potential interest of obtaining G4-binders with medical radiometals (e.g., ^99mTc, ¹¹¹In, ⁶⁴Cu, ^195mPt) suitable for diagnostic and/or therapeutic applications within nuclear medicine modalities, in order to enable their theranostic potential.

SUBMITTER: Palma E

PROVIDER: S-EPMC8308583 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Metal-Based G-Quadruplex Binders for Cancer Theranostics.

Palma Elisa E Carvalho Josué J Cruz Carla C Paulo António A

Pharmaceuticals (Basel, Switzerland) 20210623 7

The ability of fluorescent small molecules, such as metal complexes, to selectively recognize G-quadruplex (G4) structures has opened a route to develop new probes for the visualization of these DNA structures in cells. The main goal of this review is to update the most recent research efforts towards the development of novel cancer theranostic agents using this type of metal-based probes that specifically recognize G4 structures. This encompassed a comprehensive overview of the most significant ...[more]

PMID: 34201682

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Project description:The selective recognition and imaging of oncogene specific G-quadruplex (GQ) structures holds great promise in the development of diagnostic therapy (theranostics) for cancer and has been challenging due to their structural dynamics and diversity. We report selective recognition of GQ by a small molecule through unique hybrid loop stacking and groove binding mode with turn on far-red fluorescence response and anticancer activity demonstrating the potential implications for GQ-targeted cancer theranostics. Methods: Biophysical investigation reveal the turn on far-red emission property of TGP18 for selective recognition of GQ. In cellulo studies including DNA damage and oxidative stress evaluation guided us to perform in vitro (3D spheroid) and in vivo (xenograft mice model) anti-cancer activity, and tumor tissue imaging to assess the theranostic potential of TGP18. Results: Neocuproine-based far-red turn on fluorescence probe TGP18 shows GQ-to-duplex selectivity and specifically recognizes BCL-2 GQ with high affinity through a unique hybrid binding mode involving loop-stacking and groove interactions. Our study reveals that the selective recognition originating from the distinct loop structure of GQ that alters the overall probe interaction and binding affinity. TGP18 binding to anti-apoptotic BCL-2 GQ ablates the pro-survival function and elicit anti-cancer activity by inducing apoptosis in cancer cells. We deciphered that inhibition of BCL-2 transcription synergized with signaling cascade of nucleolar stress, DNA damage and oxidative stress in triggering apoptosis signaling pathway. Conclusion: Intervention of GQ mediated lethality by TGP18 has translated into anti-cancer activity in both in vitro 3D spheroid culture and in vivo xenograft models of lung and breast cancer with superior efficacy for the former. In vivo therapeutic efficacy supplemented with tumor 3D spheroid and tissue imaging potential define the role of TGP18 in GQ-targeted cancer theranostics.

Project description:Copper high aspect ratio structures (CuHARS) and silver cystine nanoparticles (AgCysNPs) are two unique micro/nano particles under study here that show extensive anti-cancer effects on a glioma tumor cell line. These micro/nano particles have shown potent toxicity in the presence of inflammatory stimulus (combination of tumor necrosis factor, [TNF] and lipo-polysaccharide, LPS). CuHARS with a concentration of 20 μg/ml uniquely increased the catalytic generation of nitric oxide (NO), an important contributor in the immune system. This NO was generated in a cell culture tumor microenvironment (TME) in the presence of 25 µM S-nitrosothiol (cysteine-NO) and the inflammatory stimulus. CuHARS increased the NO production by 68.75% when compared to untreated glioma cells with CysNO and inflammatory stimulus. The production of NO was significantly higher under similar circumstances in the case of normal primary structural cells like brain microvascular endothelial cells (BMVECs). The production of NO by BMVECs went up by 181.25% compared to glioma cells. This significant increase in the NO concentration could have added up to tumorigenesis but the anti-cancer effect of CuHARS was prominent enough to lower down the viability of glioma cells by approximately 20% and increased the metabolism of structural cells, BMVECs by approximately 200%. The immunomodulatory effect of NO in the TME under these circumstances in the presence of the novel micro/nano material, CuHARS has risen up compared to the effect of inflammatory stimulus alone. The potency and specific nature of these materials toward tumor cells may make them suitable candidates for cancer treatment. Successive treatment of CuHARS to glioma cells also proved to be an effective approach considering the decrease in the total count of cells by 11.84 fold in case of three successive treatments compared to a single dose which only decreased the cell count by 2.45 fold showing the dose-dependent increasing toxicity toward glioma cells. AgCysNPs are another potent nanomaterial which also proved its significant toxic nature toward tumor cell lines as demonstrated here, but their immunomodulatory response is still unclear and needs to be explored further.

Dataset Information

Metal-Based G-Quadruplex Binders for Cancer Theranostics.

Publications

Metal-Based G-Quadruplex Binders for Cancer Theranostics.

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