Oxidative nucleophilic substitution selectively produces cambinol derivatives with antiproliferative activity on bladder cancer cell lines

Botta, Lorenzo; Filippi, Silvia; Bizzarri, Bruno Mattia; Meschini, Roberta; Caputo, Manuela; Proietti-De-Santis, Luca; Iside, Concetta; Nebbioso, Angela; Gualandi, G; Saladino, Raffaele

doi:10.1016/j.bmcl.2018.11.006

Cited by 11 publications

(8 citation statements)

References 35 publications

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“…To date, the physiological SIRT inhibitor (SIRTi) nicotinamide (NAM) [15] and several other structurally unrelated SIRTi have been reported [16,17]. Although few SIRTi have been well characterized, some of these compounds such as EX527 [18,19], cambinol [20,21], salermide [22,23], UVI5008 [24,25], and tenovins [26,27] exhibit potential anticancer activity in specific contexts. Recently, we identified a novel pan-SIRTi, MC2494, with enhanced tumor-selective potential in vitro, ex vivo, and in vivo in both xenograft and allograft cancer models [28].…”

Section: Introductionmentioning

confidence: 99%

Enzymatic and Biological Characterization of Novel Sirtuin Modulators against Cancer

Carafa

Poziello

Torre

et al. 2019

IJMS

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Sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylases, are promising targets for anticancer treatment. Recently, we characterized a novel pan-sirtuin (SIRT) inhibitor, MC2494, displaying antiproliferative effects and able to induce death pathways in several human cancer cell lines and decrease tumor growth in vivo. Based on the chemical scaffold of MC2494, and by applying a structure–activity relationship approach, we developed a small library of derivative compounds and extensively analyzed their enzymatic action at cellular level as well as their ability to induce cell death. We also investigated the effect of MC2494 on regulation of cell cycle progression in different cancer cell lines. Our investigations indicated that chemical substitutions applied to MC2494 scaffold did not confer higher efficacy in terms of biological activity and SIRT1 inhibition, but carbethoxy-containing derivatives showed higher SIRT2 specificity. The carbethoxy derivative of MC2494 and its 2-methyl analog displayed the strongest enzymatic activity. Applied chemical modifications improved the enzymatic selectivity of these SIRT inhibitors. Additionally, the observed activity of MC2494 via cell cycle and apoptotic regulation and inhibition of cell migration supports the potential role of SIRTs as targets in tumorigenesis and makes SIRT-targeting molecules good candidates for novel pharmacological approaches in personalized medicine.

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Section: Introductionmentioning

confidence: 99%

Enzymatic and Biological Characterization of Novel Sirtuin Modulators against Cancer

Carafa

Poziello

Torre

et al. 2019

IJMS

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“…Moreover, further studies to increase the potency and selectivity towards SIRT1 or SIRT2 for enhanced their antitumor efficacy are underway. Cambinol analogs may be beneficial for sensitizing tumor cells to other chemotherapeutic agents (37,38). Thus, cambinol and its analogs are promising antitumor agents for MM.…”

Section: Discussionmentioning

confidence: 99%

Targeting SIRT1 to inhibit the proliferation of multiple myeloma cells

et al. 2021

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Multiple myeloma (MM) is the second most common hematopoietic malignancy and remains an incurable disease. Thus, novel drugs and therapeutic methods are required for patients with MM. The present study aimed to investigate the effect of sirtuin 1 (SIRT1) inhibitor cambinol on the proliferation and apoptosis of myeloma cell lines, RPMI8226 and U266. Moreover, the present study evaluated the underlying molecular mechanisms of proliferation inhibition and apoptosis induced by cambinol. A Cell Counting Kit-8 assay was used to measure the viability of RPMI8226 and U266 cells treated with cambinol. Apoptosis and the cell cycle were analyzed via flow cytometry. The expression levels of caspase-3, poly(ADP-ribose) polymerase 1 (PARP), p53, acetylated p53 (Ac-p53), Bcl-2, cyclin D1 and p21 were detected in cells treated with cambinol using western blot analysis. The results demonstrated that cambinol inhibited the proliferation of RPMI8226 and U266 cells in a time- and dose-dependent manner. Increased apoptosis and G 1 cell cycle arrest, together with enhanced procaspase-3 degradation and PARP cleavage were identified in cambinol-treated cells compared with controls. Western blotting results also revealed the upregulation of p53 acetylation and p21, as well as the downregulation of Bcl-2 and cyclin D1 in cells treated with cambinol. In conclusion, the present results suggest that cambinol inhibits the proliferation and induces apoptosis in RPMI8226 and U266 cells by regulating acetylation of p53 via the targeting of SIRT1.

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“…RIPA Buffer (20–40 μL) was added to a pellet for each species to extract proteins, incubating the solution for 15 min in ice. The cell lysates were centrifuged at 13,000 rpm for 5 min and the supernatant containing the proteins was recovered, according to Botta et al 2019 [ 99 ]. Proteins were quantified at Qubit ® 3.0 fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) and 25–30 μg protein samples were analyzed by immunoblotting on 10% SDS-PAGE as previously described [ 100 ].…”

Section: Methodsmentioning

confidence: 99%

Transcriptomic Characterization of Cow, Donkey and Goat Milk Extracellular Vesicles Reveals Their Anti-Inflammatory and Immunomodulatory Potential

Mecocci

Pietrucci

Milanesi

et al. 2021

IJMS

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Milk extracellular vesicles (mEVs) seem to be one of the main maternal messages delivery systems. Extracellular vesicles (EVs) are micro/nano-sized membrane-bound structures enclosing signaling molecules and thus acting as signal mediators between distant cells and/or tissues, exerting biological effects such as immune modulation and pro-regenerative activity. Milk is also a unique, scalable, and reliable source of EVs. Our aim was to characterize the RNA content of cow, donkey, and goat mEVs through transcriptomic analysis of mRNA and small RNA libraries. Over 10,000 transcripts and 2000 small RNAs were expressed in mEVs of each species. Among the most represented transcripts, 110 mRNAs were common between the species with cow acting as the most divergent. The most represented small RNA class was miRNA in all the species, with 10 shared miRNAs having high impact on the immune regulatory function. Functional analysis for the most abundant mRNAs shows epigenetic functions such as histone modification, telomere maintenance, and chromatin remodeling for cow; lipid catabolism, oxidative stress, and vitamin metabolism for donkey; and terms related to chemokine receptor interaction, leukocytes migration, and transcriptional regulation in response to stress for goat. For miRNA targets, shared terms emerged as the main functions for all the species: immunity modulation, protein synthesis, cellular cycle regulation, transmembrane exchanges, and ion channels. Moreover, donkey and goat showed additional terms related to epigenetic modification and DNA maintenance. Our results showed a potential mEVs immune regulatory purpose through their RNA cargo, although in vivo validation studies are necessary.

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Oxidative nucleophilic substitution selectively produces cambinol derivatives with antiproliferative activity on bladder cancer cell lines

Cited by 11 publications

References 35 publications

Enzymatic and Biological Characterization of Novel Sirtuin Modulators against Cancer

Enzymatic and Biological Characterization of Novel Sirtuin Modulators against Cancer

Targeting SIRT1 to inhibit the proliferation of multiple myeloma cells

Transcriptomic Characterization of Cow, Donkey and Goat Milk Extracellular Vesicles Reveals Their Anti-Inflammatory and Immunomodulatory Potential

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