Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Maksimović‐Ivanić, Danijela; Mijatović, Sanja; Harhaji, Ljubica; Miljković, Danijela; Dabideen, Darrin; Cheng, Kai; Mangano, Katia; Malaponte, Graziella; Al‐Abed, Yousef; Libra, Massimo; Garotta, Gianni; Nicoletti, Ferdinando; Stošić‐Grujičić, Stanislava

doi:10.1158/1535-7163.mct-07-2037

Cited by 68 publications

(53 citation statements)

References 39 publications

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“…Measurement of NO Release and Nitrite Accumulation Nitrite accumulation, as an indirect measure of NO release, was measured using the Griess reaction as described previously (20). For intracellular NO detection, the cells were stained for 1 h at 37°C with 2 μmol/L of the NO indicator DAF-FM-diacetate (Molecular Probes) in phenol redfree RPMI 1640.…”

Section: Cell Cycle Distribution and Determination Of Cell Proliferationmentioning

confidence: 99%

“…Cell-Based ELISA To measure the expression of galactocerebroside, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), cyclin D3, p53, and p-Akt, we used a slight modification of the method for cell-based ELISA (cELISA) described by Maksimovic-Ivanic et al (20). Briefly, at the end of the cultivation period, cells were fixed in 4% paraformaldehyde, and the endogenous peroxidase was quenched with 1% H 2 O 2 in PBS containing 0.1% Triton X-100 (PBST).…”

Section: Cell Cycle Distribution and Determination Of Cell Proliferationmentioning

confidence: 99%

“…Mice were sacrificed on day 30, at which time tumor growth was quantified by threedimensional measurements of individual tumors from each mouse. Tumor volume was calculated according to the following formula: 0.52 × a × b 2 , where a is the longest diameter and b is the shortest diameter (20).…”

Section: Induction Of Melanoma and Drug Treatment Of Micementioning

confidence: 99%

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The antitumor properties of a nontoxic, nitric oxide–modified version of saquinavir are independent of Akt

Maksimović‐Ivanić

Mijatović

Miljković

et al. 2009

Molecular Cancer Therapeutics

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Application of the HIV protease inhibitor saquinavir (Saq) to cancer chemotherapy is limited by its numerous side effects. To overcome this toxicity, we modified the original compound by covalently attaching a nitric oxide (NO) group. We compared the efficacy of the parental and NOmodified drugs in vitro and in vivo. The novel compound saquinavir-NO (Saq-NO) significantly reduced the viability of a wide spectrum of human and rodent tumor cell lines at significantly lower concentration than the unmodified drug.

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Section: Cell Cycle Distribution and Determination Of Cell Proliferationmentioning

confidence: 99%

Section: Cell Cycle Distribution and Determination Of Cell Proliferationmentioning

confidence: 99%

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The antitumor properties of a nontoxic, nitric oxide–modified version of saquinavir are independent of Akt

Maksimović‐Ivanić

Mijatović

Miljković

et al. 2009

Molecular Cancer Therapeutics

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“…DAF-FM diacetate and DHR stainings were employed for detection of NO and ROS/RNS [60][61][62][63]. Osteoblasts were cultivated on six surfaces of different topographies and intracellular levels of NO and ROS/RNS were examined.…”

Section: Production Of No and Ros/rns In Large Granular Cellsmentioning

confidence: 99%

Ti-SLActive and TiZr-SLActive Dental Implant Surfaces Promote Fast Osteoblast Differentiation

et al. 2017

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A primary goal in modern surface modification technology of dental implants is to achieve biocompatible surfaces with rapid but controlled healing which also allow health and longevity of implants. In order to realize all, understanding of osseointegration phenomena is crucial. Although Ti-SLA, Ti-SLActive and TiZr-SLActive surfaces have been successfully used in clinical implantology and were shown to notably reduce the primary healing time, available in vitro studies are sparse and do not concern or explore the mechanism(s) involved in human osteoblast behavior on these surfaces. Ti-SLA, Ti-SLActive, TiZr-SLActive, Ti cp, Ticer and Cercon surfaces were used. Osteoblast proliferation, cell cluster formation, morphological changes, induction of autophagy, nitric oxide (NO), reactive oxygen species/reactive nitrogen species (ROS/RNS) formation, osteocalcin (OC), bone sialoprotein (BSP) and collagen type I (Col-1) affected by various surfaces were analyzed. These surfaces induced formation of mature osteoblasts caused by elevated oxidative stress (ROS) followed by overexpression of osteoblast maturation key molecule (NO), with different intensity however. These mature osteoblasts induced upregulation of OC, BSP and Col-1, activating PI3/Akt signalling pathway resulting in autophagy, known as an important process in differentiation of osteoblast cells. Additional distinctive subpopulation identified on Ticer, Ti-SLA (after 5 days), Ti-SLActive and TiZr-SLActive surfaces (after 2 days) were forming cell clusters, essential for bone noduli formation and mineralisation. The results suggest that Ti-and TiZr-SLActive possess advanced properties in comparison with Ticer and Ti-SLA manifested as accelerated osteoblast differentiation. These effects could explain already known fast osseointegration of these surfaces in vivo.

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“…22) As an important class of NO donors, furoxans such as phenylsulfonylfuroxans are thermally stable compounds and can produce high levels of NO in vitro and inhibit the growth of tumors in vivo. 23) Furthermore, it was reported that tumor cells are more sensitive to relative high concentration of NO than normal cells and a variety of phenylsulfonylfuroxan-based NO releasing compounds have been investigated to show selective antitumor activity in vitro and in vivo. [23][24][25][26][27] It is known that the Class I enzyme HDAC2 can be directly or indirectly modified by NO, undergoing either Tyr-nitration or S-nitrosylation.…”

mentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Nitro Oxide Donating N-Hydroxycinnamamide Derivatives as Histone Deacetylase Inhibitors

Yuan

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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Novel nitro oxide (NO)-donating N-hydroxycinnamamide derivatives 12a-j were designed and synthesized by coupling the carboxyl group of N-hydroxycinnamamides with phenylsulfonylfuroxan through various diols or alkylol amines, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed good histone deacetylases (HDACs) inhibition and anti-tumor activities, particularly for 12j, which had great HDACs inhibitory activities (IC 50 s 0.15-0.26 µM) and antiproliferative effects (IC 50 s 3.21-7.12 µM) comparable to suberoylanilide hydroxamic acid (SAHA) (IC 50 s 0.16-1.41 µM for HDACs, IC 50 s 3.15-7.45 µM for cancer cell inhibition). Furthermore, compound 12j with strong antitumor activities produced high levels of NO (up to 8.0 µM of nitrites/nitrates) in colon cancer cells, and its antiproliferative activity was nearly half-diminished by hemoglobin (10 µM), an NO scavenger. These results suggest that the strong antiproliferative activity of 12j could be attributed to the additive effects of high levels of NO production and inhibition of HDAC in the cancer cells.Key words nitro oxide; histone deacetylase inhibitor; furoxan; N-hydroxycinnamamide; anti-tumor agent Pharmacological targeting of proteins that regulate epigenetics has emerged as a promising therapeutic area of study.1,2) Epigenetic or chromatin modification is recognized by nonhistone proteins and is a code of gene expression. Among the various histone modifiers, Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are two reversible enzymes regulating histone acetylation status and executing the acetylation and deacetylation of the lysine residues at the amino terminal of histones.3) However, abnormal HDAC overexpression has been found to be involved in the development of several kinds of human cancers, including myeloid neoplasia and solid tumors. 4) Recent studies have shown that acetylation of non-histone proteins is also relevant for tumorigenesis, cancer cell proliferation, and immune functions.5) Consequently, histone deacetylases are considered to be important targets in the development of anticancer agents, and in recent years considerable attention has been paid to HDAC inhibitors (HDACI) as anticancer agents. [6][7][8] There has been a high level of interest in developing smallmolecule HDACI, and numerous structurally diverse HDACI have been developed as potential anticancer agents, which are grouped chemically into four classes: hydroxamic acids, benzamides, cyclic tetrapeptides, and short-chain fatty acids.9) The common pharmacophore of these HDACI consists of three domains: a zinc-binding group (ZBG), such as hydroxamic acid; a cap group, generally a hydrophobic and aromatic group; a saturated or unsaturated linker domain, composed of linear or cyclic structures that connect the ZBG and the cap group. Up to now, two of these HDACI, suberoylanilide hydroxamic acid (SAHA, Fig. 1) and cyclic peptide Romidepsin (FK228), have been approved by the U.S. Food and Drug Administration (FDA) f...

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Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

Cited by 68 publications

References 39 publications

The antitumor properties of a nontoxic, nitric oxide–modified version of saquinavir are independent of Akt

The antitumor properties of a nontoxic, nitric oxide–modified version of saquinavir are independent of Akt

Ti-SLActive and TiZr-SLActive Dental Implant Surfaces Promote Fast Osteoblast Differentiation

Design, Synthesis and Biological Evaluation of Nitro Oxide Donating <i>N</i>-Hydroxycinnamamide Derivatives as Histone Deacetylase Inhibitors

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