Novel piplartine-containing ruthenium complexes: synthesis, cell growth inhibition, apoptosis induction and ROS production on HCT116 cells

Abstract

Piplartine (piperlongumine) is a plant-derived molecule that has been receiving intense interest due to its anticancer characteristics that target the oxidative stress. In the present paper, two novel piplartine-containing ruthenium complexes [Ru(piplartine)(dppf)(bipy)](PF6)2 (1) and [Ru(piplartine)(dppb)(bipy)](PF6)2 (2) were synthesized and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes are more potent than metal-free piplartine in a panel of cancer cell lines on monolayer cultures, as well in 3D model of cancer multicellular spheroids formed from human colon carcinoma HCT116 cells. Mechanistic studies uncovered that the complexes reduced the cell growth and caused phosphatidylserine externalization, internucleosomal DNA fragmentation, caspase-3 activation and loss of the mitochondrial transmembrane potential on HCT116 cells. Moreover, the pre-treatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced the complexes-induced apoptosis, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. Treatment with the complexes also caused a marked increase in the production of reactive oxygen species (ROS), including hydrogen peroxide, superoxide anion and nitric oxide, and decreased reduced glutathione levels. Application of N-acetyl-cysteine, an antioxidant, reduced the ROS levels and apoptosis induced by the complexes, indicating activation of ROS-mediated apoptosis pathway. RNA transcripts of several genes, including gene related to the cell cycle, apoptosis and oxidative stress, were regulated under treatment. However, the complexes failed to induce DNA intercalation. In conclusion, the complexes are more potent than piplartine against different cancer cell lines and are able to induce caspase-dependent and mitochondrial intrinsic apoptosis on HCT116 cells by ROS-mediated pathway.

Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo

“…The previous research indicates that ruthenium(II) complexes have different effects on the induction of apoptosis in SW480 cells, depending on the ligands in their structure, from a very strong impact where 72% cells were in apoptosis, to moderate, with only 31% apoptotic cells [ 27 ]. In terms of the results related to the ability of ruthenium(II) complexes to induce apoptosis of HCT116 cells, there are results from the previous research that confirm that ruthenium(II) complexes increase the early and late apoptosis of HCT116 in a time- and concentration-dependent manners, but less than oxaliplatin, which is consistent with our results [ 26 , 28 , 29 ].…”

“…These results are in accordance with previous reports that ruthenium(II) polypyridyl complexes at lower concentrations do not affect the release of LDH enzyme from various tumor cells (HeLa, PC3, LanCap, MCF-7, and MD-MBA 231), but when the cells were treated with higher concentrations of ruthenium(II) polypyridyl complexes, the LDH activity in the culture media increased significantly [ 25 ]. However, the percentages of necrotic cells remain generally low after exposure of colorectal tumor cells to piplartine and arene ruthenium(II) complexes [ 26 , 27 ].…”

Heterometallic Multinuclear Complexes as Anti‐Cancer Agents‐An Overview of Recent Developments

“…More recently, Costa et al reported the incorporation of piplartine into a Ru‐Fe complex 86 (Figure ). Piplartine is a plant‐derived molecule with anti‐cancer activity and causes oxidative stress within the cancer cell as a mode of action.…”

“…The Ru‐Fe complexes investigated by Chakraborty and colleagues ( 74 – 85 ), Costa et al ( 86 ) and Batista and colleagues ( 87 – 90 ). The IC 50 (µM) values reported are shown below the chemical structures.…”

Development of a method for quantitative determination of the cytotoxic agent piplartine (piperlongumine) in multiple skin layers

“…Piplartine (Figure ) is an amide alkaloid component of Piper species that is widely distributed in the tropical and subtropical regions of the world with commercial, economic and medicinal importance (Bezerra et al, ; Bezerra et al, ). Piplartine has shown cytotoxic and antiproliferative activity in several tumor cell lines, including melanoma (Bezerra et al, ; D’Sousa Costa et al, ). The cytotoxic effect of piplartine seems to be related to DNA damage, leading to cell death both by apoptosis and by necrosis, depending on the concentration used (Bezerra et al, ).…”