Mutagenic assessment of chemotherapy and Smac mimetic drugs in cells with defective DNA damage response pathways

Miles, Mark A.; Hawkins, Christine J.

doi:10.1038/s41598-018-32517-9

Cited by 10 publications

(5 citation statements)

References 96 publications

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“…SM-mediated killing has been attributed to endogenous TNF in cancer cells 45 , 46 ; however, it has been reported to be independent of TNF in some cancer cells 60 and HIV-infected T cells 32 . While TNF-mediated SM-induced killing in U1 undifferentiated and PMA-differentiated cells, it was not observed in primary MDMs.…”

Section: Discussionmentioning

confidence: 99%

Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages

Caballero

Dong

Gajanayaka

et al. 2021

Sci Rep

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Macrophages serve as viral reservoirs due to their resistance to apoptosis and HIV-cytopathic effects. We have previously shown that inhibitor of apoptosis proteins (IAPs) confer resistance to HIV-Vpr-induced apoptosis in normal macrophages. Herein, we show that second mitochondrial activator of caspases (SMAC) mimetics (SM) induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, chronically infected U1 cells, and ex-vivo derived MDMs from HIV-infected individuals. To understand the mechanism governing SM-induced cell death, we show that SM-induced cell death of primary HIV-infected macrophages was independent of the acquisition of M1 phenotype following HIV infection of macrophages. Instead, SM-induced cell death was found to be mediated by IAPs as downregulation of IAPs by siRNAs induced cell death of HIV-infected macrophages. Moreover, HIV infection caused receptor interacting protein kinase-1 (RIPK1) degradation which in concert with IAP1/2 downregulation following SM treatment may result in apoptosis of macrophages. Altogether, our results show that SM selectively induce apoptosis in primary human macrophages infected in vitro with HIV possibly through RIPK1. Moreover, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.

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Section: Discussionmentioning

confidence: 99%

Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages

Caballero

Dong

Gajanayaka

et al. 2021

Sci Rep

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“…Smac mimetics are commonly used in vitro to activate necroptotic pathways when combined with TNFα and an inhibitor that targets caspase-8, so we used this approach to specifically interrogate the mutagenic potential of necroptotic signaling. We observed that sublethal exposure to Smac mimetics without concurrent TNFα treatment was non-mutagenic 34,50 . We recently discovered that those treatments triggered a lytic, non-apoptotic and non-necroptotic mode of death 32 .…”

Section: Discussionmentioning

confidence: 87%

In vitro analysis reveals necroptotic signaling does not provoke DNA damage or HPRT mutations

Miles

Hawkins

2020

Cell Death Dis

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Most anticancer drugs provoke apoptotic signaling by damaging DNA or other means. Genotoxic therapies may enhance a patient's risk of developing "therapy-related cancers" due to the accumulation of oncogenic mutations that may occur in noncancerous cells. Mutations can also form upon apoptotic signaling due to sublethal caspase activity, implying that apoptosis activating drugs may also be oncogenic. Necroptosis is a different way of killing cancer cells: this version of caspase-independent cell death is characterized by receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase-like domain protein (MLKL) activation, leading to cell membrane rupture and controlled cell lysis. The mutagenic potential of sublethal necroptotic signaling has not yet been directly investigated. Smac mimetics drugs, which activate apoptotic or necroptotic cell death, do not induce mutations but the mechanistic basis for this lack of mutagenic activity has not been determined. In this study, we compared the mutagenic potential of these two cell death pathways by engineering cells to activate either apoptotic or necroptotic signaling by exposing them to Smac mimetics with or without TNFα, and/or enforcing or preventing expression of apoptotic or necroptotic regulators. We discovered that sublethal concentrations of Smac mimetics in contexts that activated apoptotic signaling provoked DNA damage and mutations in surviving cells. Mutagenesis was dependent on executioner caspase activation of the nuclease CAD. In contrast, RIPK3-and MLKL-dependent necroptotic signaling following Smac mimetic treatment was not mutagenic. Likewise, DNA damage was not provoked in cells expressing a lethal constitutively active MLKL mutant. These data reveal that cells surviving sublethal necroptotic signaling do not sustain genomic damage and provide hope for a reduced risk of therapy-related malignancies in patients treated with necroptosis-inducing drugs.

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“…This feature may be especially beneficial for cancer patients with germline flaws in DNA damage response pathways, for whom mutagenic therapies would be particularly risky. As yet, no anti-cancer agents have been created that exclusively trigger necroptosis, but Smac mimetic treatment (which can provoke apoptotic or necroptotic cell death) was non-mutagenic in vitro, even when accurate DNA repair was compromised [ 199 ]. Further research will be needed to define the mutagenicity associated with sublethal activation of more recently described cell death pathways, including pyroptosis and ferroptosis, and the prospects for therapeutic exploitation of these pathways.…”

Section: Discussionmentioning

confidence: 99%

“…H2AX was phosphorylated primarily by DNA-PK following TRAIL treatment [ 160 ]. Mutation frequencies were dramatically reduced in DNA-PKcs-deficient cells following exposure to chemotherapies doxorubicin and cisplatin, and vincristine, the mutagenesis of which was caspase/CAD-dependent [ 199 ]. This further highlights the mutagenic potential of NHEJ machinery and also directly implicates the requirement of error-prone repair pathways in CAD mutagenesis.…”

Section: Mutagenic Consequences Of Apoptotic Signalingmentioning

confidence: 99%

Mutagenic Consequences of Sublethal Cell Death Signaling

Hawkins

Miles

2021

IJMS

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Many human cancers exhibit defects in key DNA damage response elements that can render tumors insensitive to the cell death-promoting properties of DNA-damaging therapies. Using agents that directly induce apoptosis by targeting apoptotic components, rather than relying on DNA damage to indirectly stimulate apoptosis of cancer cells, may overcome classical blocks exploited by cancer cells to evade apoptotic cell death. However, there is increasing evidence that cells surviving sublethal exposure to classical apoptotic signaling may recover with newly acquired genomic changes which may have oncogenic potential, and so could theoretically spur the development of subsequent cancers in cured patients. Encouragingly, cells surviving sublethal necroptotic signaling did not acquire mutations, suggesting that necroptosis-inducing anti-cancer drugs may be less likely to trigger therapy-related cancers. We are yet to develop effective direct inducers of other cell death pathways, and as such, data regarding the consequences of cells surviving sublethal stimulation of those pathways are still emerging. This review details the currently known mutagenic consequences of cells surviving different cell death signaling pathways, with implications for potential oncogenic transformation. Understanding the mechanisms of mutagenesis associated (or not) with various cell death pathways will guide us in the development of future therapeutics to minimize therapy-related side effects associated with DNA damage.

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Mutagenic assessment of chemotherapy and Smac mimetic drugs in cells with defective DNA damage response pathways

Cited by 10 publications

References 96 publications

Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages

Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages

In vitro analysis reveals necroptotic signaling does not provoke DNA damage or HPRT mutations

Mutagenic Consequences of Sublethal Cell Death Signaling

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