Cyclometalated Ir(<scp>iii</scp>) complexes as targeted theranostic anticancer therapeutics: combining HDAC inhibition with photodynamic therapy

Ye, Rui-Rong; Tan, Cai‐Ping; He, Liangmei; Chen, Mu-He; Ji, Liang‐Nian; Mao, Zong‐Wan

doi:10.1039/c4cc05215c

Cited by 117 publications

(64 citation statements)

References 38 publications

(17 reference statements)

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“…One study recently reported that HDACis potentiate UVA-mediated phototherapy of T cell lymphoma [35], but UVA itself is known to be a risk factor for cancer [36]. The mechanism of coupling HDAC inhibition to PDT seems to have recently captured the interest of synthetic chemistry wherein two independent studies have each synthesized one new compound possessing both photoactivation and HDAC inhibitory potentials [37, 38]. Combination of PDT with HDAC inhibition represents a novel approach, with potentially promising outcomes, in cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we attempted to overcome CRC cell resistance to HY-PDT by pretreatment with HDACis especially that the latter are non-genotoxic agents and can epigenetically sensitize cells to external stimuli. The mechanism of coupling HDAC inhibition to PDT seems to have recently captured the interest of synthetic chemistry wherein two independent studies have each synthesized one new compound possessing both photoactivation and HDAC inhibitory potentials [37, 38]. We tested two chemical groups of HDACis: (a) the hydroxamic acids, which are inhibitors of all classes of HDACs, and (b) the short-chain fatty acids, which are inhibitors of predominantly nuclear HDACs.…”

Section: Methodsmentioning

confidence: 99%

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Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A

et al. 2017

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BackgroundHypericin-mediated photodynamic therapy (HY-PDT) has recently captured increased attention as an alternative minimally invasive anticancer treatment, although cancer cells may acquire resistance. Therefore, combination treatments may be necessary to enhance HY-PDT efficacy. Histone deacetylase inhibitors (HDACis) are often used in combination treatments due to their non-genotoxic properties and epigenetic potential to sensitize cells to external stimuli. Therefore, this study attempts for the first time to investigate the therapeutic effects of HDACis in combination with visible light-mediated PDT against cancer. Specifically, the colorectal cancer cell model was used due to its known resistance to HY-PDT.ResultsTwo chemical groups of HDACis were tested in combination with HY-PDT: the hydroxamic acids Saha and Trichostatin A, and the short-chain fatty acids valproic acid and sodium phenylbutyrate (NaPB), as inhibitors of all-class versus nuclear HDACs, respectively. The selected HDACis manifest a favorable clinical toxicity profile and showed similar potencies and mechanisms in intragroup comparisons but different biological effects in intergroup analyses. HDACi combination with HY-PDT significantly attenuated cancer cell resistance to treatment and caused the two HDACi groups to become similarly potent. However, the short-chain fatty acids, in combination with HY-PDT, showed increased selectivity towards inhibition of HDACs versus other key epigenetic enzymes, and NaPB induced the strongest expression of the otherwise silenced tumor suppressor CDKN1A, a hallmark gene for HDACi-mediated chromatin modulation. Epigenetic regulation of CDKN1A by NaPB was associated with histone acetylation at enhancer and promoter elements rather than histone or DNA methylation at those or other regulatory regions of this gene. Moreover, NaPB, compared to the other HDACis, caused milder effects on global histone acetylation, suggesting a more specific effect on CDKN1A chromatin architecture relative to global chromatin structure. The mechanism of NaPB + HY-PDT was P53-dependent and likely driven by the HY-PDT rather than the NaPB constituent.ConclusionsOur results show that HDACis potentiate the antitumor efficacy of HY-PDT in colorectal cancer cells, overcoming their resistance to this drug and epigenetically reactivating the expression of CDKN1A. Besides their therapeutic potential, hypericin and these HDACis are non-genotoxic constituents of dietary agents, hence, represent interesting targets for investigating mechanisms of dietary-based cancer prevention.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0359-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A

et al. 2017

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“…11–17 The resistance of tumors to platinum decreases the efficacy of platinum-based or even renders them ineffective, causing treatment failure. 18–22 In the design of new anticancer drugs, 23–29 the ruthenium complexes have raised great interest and have been tested against a number of cancer cell lines, 30–36 and are regarded as promising candidates for alternative drugs to cisplatin and its derivatives.…”

Section: Introductionmentioning

confidence: 99%

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

et al. 2017

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Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. The ruthenium(III) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(II) complexes have also attracted significant attention as anticancer candidates; however, only few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(II) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(II)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(II) complexes, their targeted delivery, and their activity in nanomaterial systems.

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“…On the other hand, cyclometalated Ir(III) complexes are also considered to be potent anticancer candidates as they can target subcellular organelles, inhibit protein activities and act as photodynamic therapeutic agents11121314151617. Our group has endeavored to develop cyclometalated Ir(III) complexes as multifunctional theranostic agents integrating anticancer properties and imaging capabilities14151617.…”

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Ester-Modified Cyclometalated Iridium(III) Complexes as Mitochondria-Targeting Anticancer Agents

Wang

Chen

et al. 2016

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Organometallic iridium complexes are potent anticancer candidates which act through different mechanisms from cisplatin-based chemotherapy regimens. Here, ten phosphorescent cyclometalated iridium(III) complexes containing 2,2′-bipyridine-4,4′-dicarboxylic acid and its diester derivatives as ligands are designed and synthesized. The modification by ester group, which can be hydrolysed by esterase, facilitates the adjustment of drug-like properties. The quantum yields and emission lifetimes are influenced by variation of the ester substituents on the Ir(III) complexes. The cytotoxicity of these Ir(III) complexes is correlated with the length of their ester groups. Among them, 4a and 4b are found to be highly active against a panel of cancer cells screened, including cisplatin-resistant cancer cells. Mechanism studies in vitro indicate that they undergo hydrolysis of ester bonds, accumulate in mitochondria, and induce a series of cell-death related events mediated by mitochondria. Furthermore, 4a and 4b can induce pro-death autophagy and apoptosis simultaneously. Our study indicates that ester modification is a simple and feasible strategy to enhance the anticancer potency of Ir(III) complexes.

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Cyclometalated Ir(iii) complexes as targeted theranostic anticancer therapeutics: combining HDAC inhibition with photodynamic therapy

Abstract: The successful design and anticancer mechanistic studies of a series of cyclometalated Ir(III) complexes with histone deacetylase inhibitory and photodynamic therapy (PDT) activities are reported.

Cited by 117 publications

References 38 publications

Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A

Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

Ester-Modified Cyclometalated Iridium(III) Complexes as Mitochondria-Targeting Anticancer Agents

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