Human topoisomerase inhibition and DNA/BSA binding of Ru(II)–SCAR complexes as potential anticancer candidates for oral application

Grandis, Rone Aparecido De; Camargo, Margarete; Silva, Monize M. da; Lopes, Érica O; Padilha, Elias Carvalho; Resende, Flávia Aparecida; Peccinini, Rosângela Gonçalves; Pavan, Fernando Rogério; Desideri, Alessandro; Batista, Alzir A.; Varanda, Eliana Aparecida

doi:10.1007/s10534-017-0008-z

Cited by 26 publications

(5 citation statements)

References 58 publications

(61 reference statements)

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“…Sk-OV-3 cells, however, were shown to be resistant against both 7-HC and Cisplatin treatment (IC 50 >100 µg/mL). The IC 50 values of Cisplatin on the same cancer cell lines are in agreement with the literature 26,27 . In an attempt to achieve an improved therapeutic outcome, all 4 cell lines were subjected to a combination of 7-HC and the conventional antineoplastic drug Cisplatin (Table 3).…”

Section: Discussionsupporting

confidence: 91%

In Vitro and In Vivo Evaluation of the Anticancer and Anti-inflammatory Activities of 2-Himachelen-7-ol isolated from Cedrus Libani

Elias

Shebaby

Nehme

et al. 2019

Sci Rep

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Cedrus libani is a majestic evergreen tree native to the Mediterranean mountains of Lebanon, Syria and Turkey. In this study, the tree heart wood was extracted using hexane to produce C. libani oil extract (CLOE) as a dark oil. GCMS analysis of CLOE identified up to 30 compounds whereby 2-himachalen-7-ol (7-HC) was the most abundant (40%). 7-HC was isolated using column chromatography and the identity of the white crystalline solid was confirmed via NMR spectroscopy and X-Ray Crystallography. 7-HC demonstrated potent cytotoxic activity against several human cancer cell lines including brain (SF-268, IC 50 8.1 μg/mL) and colon (HT-29, IC 50 10.1 μg/mL; Caco-2, IC 50 9.9 μg/mL) with ovarian (Sk-OV-3, IC 50 > 50 μg/mL) cells being the most resistant. However, while HT-29 displayed resistance to Cisplatin, 7-HC was 8–10 folds more potent. Co-treatment with 7-HC and Cisplatin showed a significant synergistic anti-proliferative effect against SF-268, HT-29 and Caco-2 cells. 7-HC also exhibited significant anti-inflammatory effect in formalin-induced paw edema in rats. Western blot analysis revealed that 7-HC displayed dose dependent inhibition of LPS-induced COX-2 protein expression in isolated rat monocytes. The present study demonstrates that 7-HC possesses promising anticancer and anti-inflammatory activities, and may serve as a lead molecule in cancer therapy.

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Section: Discussionsupporting

confidence: 91%

In Vitro and In Vivo Evaluation of the Anticancer and Anti-inflammatory Activities of 2-Himachelen-7-ol isolated from Cedrus Libani

Elias

Shebaby

Nehme

et al. 2019

Sci Rep

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“…Herein, we observed that these ruthenium complexes behave like DNA intercalating agents, which can be caused by drug-DNA interactions at the minor groove or/and electrostatic interactions. These effects can occur with octahedral compounds, such as the ruthenium complexes, that are very bulky and that do not intercalate (33, 34). A ruthenium complex containing guanidine has been reported to bind to DNA and induce DNA damage, cell cycle arrest and to activate the typical apoptosis pathways in MCF-7 cells (35).…”

Section: Discussionmentioning

confidence: 99%

Ruthenium Complexes Containing Heterocyclic Thioamidates Trigger Caspase-Mediated Apoptosis Through MAPK Signaling in Human Hepatocellular Carcinoma Cells

et al. 2019

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Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF 6 ( 1 ), [Ru(tzdt)(bipy)(dppb)]PF 6 ( 2 ), [Ru(dmp)(bipy)(dppb)]PF 6 ( 3 ) and [Ru(mpca)(bipy)(dppb)]PF 6 ( 4 ) were investigated for their cellular and molecular effects in cancer cell lines. Complexes 1 and 2 were the most potent of the four compounds against a panel of different cancer cell lines in monolayer cultures and showed potent cytotoxicity in a 3D model of multicellular spheroids that formed from human hepatocellular carcinoma HepG2 cells. In addition, both complexes were able to bind to DNA in a calf thymus DNA model. Compared to the controls, a reduction in cell proliferation, phosphatidylserine externalization, internucleosomal DNA fragmentation, and the loss of the mitochondrial transmembrane potential were observed in HepG2 cells that were treated with these complexes. Additionally, coincubation with a pan-caspase inhibitor (Z-VAD(OMe)-FMK) reduced the levels of apoptosis that were induced by these compounds compared to those in the negative controls, indicating that cell death through apoptosis occurred via a caspase-dependent pathway. Moreover, these complexes also induced the phosphorylation of ERK1/2, and coincubation with an MEK inhibitor (U0126), which is known to inhibit the activation of ERK1/2, but not JNK/SAPK and p38 MAPK inhibitors, reduced the complexes-induced apoptosis compared to that in the negative controls, indicating that the induction of apoptotic cell death occurred through ERK1/2 signaling in HepG2 cells. On the other hand, no increase in oxidative stress was observed in HepG2 cells treated with the complexes, and the complexes-induced apoptosis was not reduced with coincubation with the antioxidant N-acetylcysteine or a p53 inhibitor compared to that in the negative controls, indicating that apoptosis occurred via oxidative stress- and p53-independent pathways. Finally, these complexes also reduced the growth of HepG2 cells that were engrafted in C.B-17 SCID mice compared to that in the negative controls. These results indicated that these complexes are novel anticancer drug candidates for liver cancer treatment.

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“…Hence, within the framework of our continuous effort to design novel metallodrug candidates, in the last years, our research group has synthesized several ruthenium complexes with promising pharmacological activities for the anticancer purpose ( 22 – 26 ). In the light of those findings, herein we have investigated for once the cellular and molecular responses of two novel lapachol-containing ruthenium(II) complexes [Ru(Lap)(dppm)(bipy)]PF 6 ( 1 ) and [Ru(Lap)(dppm)(phen)]PF 6 ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells

et al. 2021

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Lapachol is a well-studied natural product that has been receiving great interest due to its anticancer properties that target oxidative stress. In the present work, two novel lapachol-containing ruthenium(II) complexes [Ru(Lap)(dppm)(bipy)]PF6 (1) and [Ru(Lap)(dppm)(phen)]PF6 (2) [Lap = lapachol, dppm = 1,1′-bis(diphosphino)methane, bipy = 2,2′-bipyridine, phen = 1,10-phenantroline] were synthesized, fully characterized, and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures, as well as in a 3D model of multicellular spheroids formed from DU-145 human prostate adenocarcinoma cells. Furthermore, the complex (2) suppressed the colony formation, induced G2/M-phase arrest, and downregulated Aurora-B. The mechanism studies suggest that complex (2) stimulate the overproduction of reactive oxygen species (ROS) and triggers caspase-dependent apoptosis as a result of changes in expression of several genes related to cell proliferation and caspase-3 and -9 activation. Interestingly, we found that N-acetyl-L-cysteine, a ROS scavenger, suppressed the generation of intracellular ROS induced by complex (2), and decreased its cytotoxicity, indicating that ROS-mediated DNA damage leads the DU-145 cells into apoptosis. Overall, we highlighted that coordination of lapachol to phosphinic ruthenium(II) compounds considerably improves the antiproliferative activities of resulting complexes granting attractive selectivity to human prostate adenocarcinoma cells. The DNA damage response to ROS seems to be involved in the induction of caspase-mediated cell death that plays an important role in the complexes' cytotoxicity. Upon further investigations, this novel class of lapachol-containing ruthenium(II) complexes might indicate promising chemotherapeutic agents for prostate cancer therapy.

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Human topoisomerase inhibition and DNA/BSA binding of Ru(II)–SCAR complexes as potential anticancer candidates for oral application

Cited by 26 publications

References 58 publications

In Vitro and In Vivo Evaluation of the Anticancer and Anti-inflammatory Activities of 2-Himachelen-7-ol isolated from Cedrus Libani

In Vitro and In Vivo Evaluation of the Anticancer and Anti-inflammatory Activities of 2-Himachelen-7-ol isolated from Cedrus Libani

Ruthenium Complexes Containing Heterocyclic Thioamidates Trigger Caspase-Mediated Apoptosis Through MAPK Signaling in Human Hepatocellular Carcinoma Cells

A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells

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