scholarly journals Synthetic prodrug design enables biocatalytic activation in mice to elicit tumor growth suppression

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Igor Nasibullin ◽  
Ivan Smirnov ◽  
Peni Ahmadi ◽  
Kenward Vong ◽  
Almira Kurbangalieva ◽  
...  

AbstractConsidering the intrinsic toxicities of transition metals, their incorporation into drug therapies must operate at minimal amounts while ensuring adequate catalytic activity within complex biological systems. As a way to address this issue, this study investigates the design of synthetic prodrugs that are not only tuned to be harmless, but can be robustly transformed in vivo to reach therapeutically relevant levels. To accomplish this, retrosynthetic prodrug design highlights the potential of naphthylcombretastatin-based prodrugs, which form highly active cytostatic agents via sequential ring-closing metathesis and aromatization. Structural adjustments will also be done to improve aspects related to catalytic reactivity, intrinsic bioactivity, and hydrolytic stability. The developed prodrug therapy is found to possess excellent anticancer activities in cell-based assays. Furthermore, in vivo activation by intravenously administered glycosylated artificial metalloenzymes can also induce significant reduction of implanted tumor growth in mice.

2016 ◽  
Vol 128 (39) ◽  
pp. 12114-12118 ◽  
Author(s):  
Tommy Tsz-Him Fong ◽  
Chun-Nam Lok ◽  
Clive Yik-Sham Chung ◽  
Yi-Man Eva Fung ◽  
Pui-Keong Chow ◽  
...  

2019 ◽  
Author(s):  
Leonard Lothstein ◽  
Judith Ellen Soberman ◽  
Deanna Parke ◽  
Jatin Gandhi ◽  
Trevor Sweatman ◽  
...  

Abstract Background: Triple-negative breast cancer (TNBC) is unresponsive to anti-estrogen and anti-HER2 therapies, requiring the use of cytotoxic drug combinations of anthracyclines, taxanes, cyclophosphamide and platinum compounds. Multidrug therapies achieve pathological cure rates of only 20-40%, a consequence of drug resistance and cumulative dose limitations necessitated by the irreversible cardiotoxic effects of anthracyclines and other cytotoxic agents. Safer and more effective treatments for TNBC are required to achieve durable therapeutic responses. This study describes the mechanism of action and in vivo efficacy of pivarubicin, a structurally and functionally novel anthracycline, to determine whether pivarubicin is potentially more effective and safer than doxorubicin against human primary TNBC. Methods: Hydrolytic stability, mechanism and ability of pivarubicin to circumvent mechanisms of resistance are tested in multiple tumor lines through modulation of PKC-delta activity and assessment of drug cytotoxicity. Comparative in vivo efficacy is tested in an orthotopic NSG mouse model implanted with MDA-MB-231 human TNBC cells and treated with the maximum tolerated doses of pivarubicin and doxorubicin, followed by monitoring of tumor growth by digital caliper measurements and determination of endpoint tumor weight and volume. Endpoint cardiotoxicity is assessed histologically by identifying microvacuolization in ventricular cardiomyocytes. Results: The trimethylester moiety of pivarubicin confers hydrolytic stability relative to the closely related congener, AD 198, but retains the ability of other N -alkylbenzyladriamycin compounds to directly activate PKC-delta and trigger rapid mitochondrial-dependent apoptosis. The structure and function of pivarubicin permits circumvention of resistance conferred by overexpression of P-glycoprotein, Bcl-2, Bcl-X L and Bcr-Abl. Primary tumors treated with the multiple rounds of the maximum tolerated dose (MTD) of doxorubicin failed to inhibit tumor growth compared with vehicle-treated tumors. However, administration of a single MTD of pivarubicin produced significant inhibition of tumor growth and tumor regression relative to tumor volume prior to initiation of treatment. Histological analysis of hearts excised from drug- and vehicle-treated mice revealed that pivarubicin produced no evidence of myocardial damage at this therapeutic dose. Conclusion: These results support the development of pivarubicin as a safer and more effective replacement for doxorubicin against TNBC as well as other malignancies for which doxorubicin therapy is indicated.


2013 ◽  
Vol 129 ◽  
pp. 127-134 ◽  
Author(s):  
Natalia I. Shtemenko ◽  
Helen T. Chifotides ◽  
Konstantin V. Domasevitch ◽  
Alexander A. Golichenko ◽  
Svetlana A. Babiy ◽  
...  

2018 ◽  
Vol 6 (1) ◽  
pp. 1801423 ◽  
Author(s):  
Qi Liu ◽  
Kai Zhao ◽  
Chun Wang ◽  
Zhanzhan Zhang ◽  
Chunxiong Zheng ◽  
...  

2015 ◽  
Vol 2015 ◽  
pp. 1-21 ◽  
Author(s):  
William M. Motswainyana ◽  
Peter A. Ajibade

Ruthenium compounds are highly regarded as potential drug candidates. The compounds offer the potential of reduced toxicity and can be tolerated in vivo. The various oxidation states, different mechanism of action, and the ligand substitution kinetics of ruthenium compounds give them advantages over platinum-based complexes, thereby making them suitable for use in biological applications. Several studies have focused attention on the interaction between active ruthenium complexes and their possible biological targets. In this paper, we review several ruthenium compounds which reportedly possess promising cytotoxic profiles: from the discovery of highly active compounds imidazolium [trans-tetrachloro(dmso)(imidazole)ruthenate(III)] (NAMI-A), indazolium [trans-tetrachlorobis(1H-indazole)ruthenate(III)](KP1019), and sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) to the recent work based on both inorganic and organometallic ruthenium(II) compounds. Half-sandwich organometallic ruthenium complexes offer the opportunity of derivatization at the arene moiety, while the three remaining coordination sites on the metal centre can be functionalised with various coordination groups of various monoligands. It is clear from the review that these mononuclear ruthenium(II) compounds represent a strongly emerging field of research that will soon culminate into several ruthenium based antitumor agents.


Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 528 ◽  
Author(s):  
Lei Gao ◽  
Chaochao Ge ◽  
Senzhen Wang ◽  
Xiaojuan Xu ◽  
Yongli Feng ◽  
...  

Colorectal cancer (CRC) is one of the most prevalent cancers due to its frequency and high rate of mortality. Polyamine-vectorized anticancer drugs possess multiple biological properties. Of these drugs, 9F has been shown to inhibit tumor growth and the metastasis of hepatocellular carcinoma. This current study aims to investigate the effects of 9F on CRC and determine its molecular mechanisms of action. Our findings demonstrate that 9F inhibits CRC cell growth by inducing apoptosis and cell cycle arrest, and suppresses migration, invasion and angiogenesis in vitro, resulting in the inhibition of tumor growth and metastasis in vivo. Based on RNA-seq data, further bioinformatic analyses suggest that 9F exerts its anticancer activities through p53 signaling, which is responsible for the altered expression of key regulators of the cell cycle, apoptosis, the epithelial-to-mesenchymal transition (EMT), and angiogenesis. In addition, 9F is more effective than amonafide against CRC. These results show that 9F can be considered as a potential strategy for CRC treatment.


2021 ◽  
Author(s):  
fan Wu ◽  
yang Liu ◽  
hui Cheng ◽  
yun Meng ◽  
yan Yi ◽  
...  

Abstract Glucose oxidase (GOx) can effectively catalyze glucose intogluconic acid and hydrogen peroxide (H2O2) in the presence of O2, which is considered as an attractive starvation strategy for cancer therapy. However, the autophagy phenomenon protects tumor cells from starvation therapy, limiting the therapy effect, thus autophagy inhibition could be used as a troubleshooting method to enhance tumor starvation therapy. Herein, biodegradable dendritic mesoporous organosilicon nanoagent (DMON) was used as the nanocarrier to deliver GOx and 3-MA (an autophagyinhibition agent), designed as DMON@GOx/3-MA. T his formulation could have a synergetic effect on autophagy inhibition and starvation therapy. All in vitro and in vivo results demonstrated that autophagy inhibition obviously enhanced the efficacy of starvation therapy, leading to tumor growth suppression. Our strategy will provide a new way to enhance the efficacy of starvation cancer therapy.


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