Targeting apoptotic caspases in cancer

Boice, Ashley; Bouchier‐Hayes, Lisa

doi:10.1016/j.bbamcr.2020.118688

Cited by 270 publications

(181 citation statements)

References 205 publications

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“…Among them, we can highlight the nuclear enzyme PARP-1, which plays a central role in DNA repair. This nuclear enzyme can be activated by some executioner caspases such as caspase-3 and caspase-7 [57][58][59][60] . The hmxbato complex was able to increase the expression of the PARP-1 enzyme in A549 cells, indicating its possible interference in the DNA of cells.…”

Section: Resultsmentioning

confidence: 99%

Ruthenium (II) complex cis-[RuII(ŋ2-O2CC7H7O2)(dppm)2]PF6-hmxbato induces ROS-mediated apoptosis in lung tumor cells producing selective cytotoxicity

Costa

Gonçalves

Borges

et al. 2020

Sci Rep

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Ruthenium complexes have been extensively explored as potential molecules for cancer treatment. Considering our previous findings on the remarkable cytotoxic activity exhibited by the ruthenium (II) complex 3-hydroxy-4-methoxybenzoate (hmxbato)-cis-[RuII(ŋ2-O2CC7H7O2)(dppm)2]PF6 against Leishmania promastigotes and also the similar metabolic characteristics between trypanosomatids and tumor cells, the present study aimed to analyze the anticancer potential of hmxbato against lung tumor cells, as well as the partial death mechanisms involved. Hmxbato demonstrated selective cytotoxicity against A549 lung tumor cells. In addition, this complex at a concentration of 3.8 µM was able to expressively increase the generation of reactive oxygen species (ROS) in tumor cells, causing an oxidative stress that may culminate in: (1) reduction in cellular proliferation; (2) changes in cell morphology and organization patterns of the actin cytoskeleton; (3) cell arrest in the G2/M phase of the cell cycle; (4) apoptosis; (5) changes in the mitochondrial membrane potential and (6) initial DNA damage. Furthermore, we demonstrated that the induction of programmed cell death can occur by the intrinsic apoptotic pathway through the activation of caspases. It is also worth highlighting that hmxbato exhibited predominant actions on A549 tumor cells in comparison to BEAS-2B normal bronchial epithelium cells, which makes this complex an interesting candidate for the design of new drugs against lung cancer.

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Section: Resultsmentioning

confidence: 99%

Ruthenium (II) complex cis-[RuII(ŋ2-O2CC7H7O2)(dppm)2]PF6-hmxbato induces ROS-mediated apoptosis in lung tumor cells producing selective cytotoxicity

Costa

Gonçalves

Borges

et al. 2020

Sci Rep

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“…Identification of alternative DNA damage response genes to target in cancer could be useful as therapies in their own right and also in cases where tumours become resistant to other therapies, such as is currently observed in BRCA-deficient tumours treated with PARP inhibitors [90,91]. Finally, ATM has widespread cellular roles outside the DNA damage response, including roles in cellular redox signalling [41] and regulation of autophagy [92,93], apoptosis and other cell death pathways [94][95][96][97][98], further increasing potential opportunities to target ATM-deficient cells with novel therapies.…”

Section: Discussionmentioning

confidence: 99%

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

Jette

Kumar

Radhamani

et al. 2020

Cancers

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Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death.

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“…Members of the Caspase family of proteases play essential roles in the initiation and execution of apoptosis. These Caspases are divided into two groups: the initiator Caspases (Caspase-2, -8, -9, and -10), which are the first to be activated in response to a signal, and the executioner Caspases (Caspase-3, -6, and -7) that carry out the demolition phase of apoptosis 36 . So we only chose Caspase 3 expression to observe the apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…7c, e). Members of the Caspase family of proteases play essential roles in the initiation (Caspase-2, -8, -9 and -10) and execution of apoptosis (Caspase-3, -6, and -7) 36 . We found that Caspase 3 expression was increased by knocking out IL-17, and decreased by giving As-IV (n = 5, Fig.…”

Section: Neural Apoptosis In Ischemic Cortex Is Ameliorated By Adminimentioning

confidence: 99%

Antagonistic effects of IL-17 and Astragaloside IV on cortical neurogenesis and cognitive behavior after stroke in adult mice through Akt/GSK-3β pathway

et al. 2020

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We aimed to investigate the exact effect of IL-17 on regulating neural stem cells (NSCs) stemness and adult neurogenesis in ischemic cortex after stroke, how Astragaloside IV(As-IV) regulated IL-17 expression and the underlying mechanism. Photochemical brain ischemia model was established and IL-17 protein expression was observed at different time after stroke in WT mice. At 3 days after stroke, when IL-17 expression peaked, IL-17 knock out (KO) mice were used to observe cell proliferation and neurogenesis in ischemic cortex. Then, As-IV was administered intravenously to assess cell apoptosis, proliferation, neurogenesis, and cognitive deficits by immunochemistry staining, western blots, and animal behavior tests in WT mice. Furthermore, IL-17 KO mice and As-IV were used simultaneously to evaluate the mechanism of cell apoptosis and proliferation after stroke in vivo. Besides, in vitro, As-IV and recombinant mouse IL-17A was administered, respectively, into NSCs culture, and then their diameters, viable cell proliferation and pathway relevant protein was assessed. The results showed knocking out IL-17 contributed to regulating PI3K/Akt pathway, promoting NSCs proliferation, and neurogenesis after ischemic stroke. Moreover, As-IV treatment helped inhibit neural apoptosis, promote the neurogenesis and eventually relieve mice anxiety after stroke. Unsurprisingly, IL-17 protein expression could be downregulated by As-IV in vivo and in vitro and they exerted antagonistic effect on neurogenesis by regulating Akt/GSK-3β pathway, with significant regulation for apoptosis. In conclusion, IL-17 exerts negative effect on promoting NSCs proliferation, neurogenesis and cognitive deficits after ischemic stroke, which could be reversed by As-IV.

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Targeting apoptotic caspases in cancer

Cited by 270 publications

References 205 publications

Ruthenium (II) complex cis-[RuII(ŋ2-O2CC7H7O2)(dppm)2]PF6-hmxbato induces ROS-mediated apoptosis in lung tumor cells producing selective cytotoxicity

Ruthenium (II) complex cis-[RuII(ŋ2-O2CC7H7O2)(dppm)2]PF6-hmxbato induces ROS-mediated apoptosis in lung tumor cells producing selective cytotoxicity

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

Antagonistic effects of IL-17 and Astragaloside IV on cortical neurogenesis and cognitive behavior after stroke in adult mice through Akt/GSK-3β pathway

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