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Selective induction of necrotic cell death in cancer cells by beta-lapachone through activation of DNA damage
Xiangao Sun1, Youzhi Li, Wei Li
1Department of Therapeutic Biology, ArQule Biomedical Institute, Norwood, Massachusetts 02062, USA.
Abstract:
Most efforts thus far have been devoted to develop apoptosis inducers for cancer treatment. However, apoptotic pathway deficiencies are a hallmark of cancer cells. We propose that one way to bypass defective apoptotic pathways in cancer cells is to induce necrotic cell death. Here we show that selective induction of necrotic cell death can be achieved by activation of the DNA damage response pathways. While beta-lapachone induces apoptosis through E2F1 checkpoint pathways, necrotic cell death can be selectively induced by beta-lapachone in a variety of cancer cells. We found that beta-lapachone, unlike DNA damaging chemotherapeutic agents, transiently activates PARP1, a main regulator of the DNA damage response pathway, both in vitro and in vivo. This occurs within minutes of exposure to beta-lapachone, resulting in selective necrotic cell death. Inhibition of PAR blocked beta-lapachone-induced necrosis. Furthermore, necrotic cell death induced by beta-lapachone was significantly reduced in PARP1 knockout cell lines. Our data suggest that selective necrotic cell death can be induced through activation of DNA damage response pathways, supporting the idea of selective necrotic cell death as a therapeutic strategy to eliminate cancer cells.
Insights
Cancer cells often evade apoptosis. This study shows beta-lapachone can selectively induce necrotic cell death by activating DNA damage response pathways, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Pathways
Background:
- Cancer cells frequently exhibit deficiencies in apoptosis, a programmed cell death pathway.
- Targeting apoptosis is a common strategy, but its ineffectiveness in some cancers necessitates alternative approaches.
- Necrotic cell death offers a potential alternative to bypass defective apoptotic mechanisms in cancer.
Purpose of the Study:
- To investigate the potential of inducing necrotic cell death to circumvent apoptosis resistance in cancer.
- To explore the role of DNA damage response pathways in mediating selective cancer cell death.
- To evaluate beta-lapachone as an agent for inducing necrotic cell death.
Main Methods:
- Treatment of various cancer cells with beta-lapachone.
- Analysis of DNA damage response pathway activation, specifically Poly (ADP-ribose) polymerase 1 (PARP1).
- Inhibition of PARP activity and use of PARP1 knockout cell lines to assess the mechanism of cell death.
Main Results:
- Beta-lapachone selectively induced necrotic cell death in diverse cancer cell types.
- The compound transiently activated PARP1 within minutes, unlike traditional DNA damaging agents.
- Inhibition of PARP or absence of PARP1 significantly reduced beta-lapachone-induced necrosis.
Conclusions:
- Activation of DNA damage response pathways, particularly PARP1, can selectively induce necrotic cell death.
- Beta-lapachone's ability to trigger PARP1-mediated necrosis presents a novel therapeutic strategy for cancer.
- Targeting necrotic cell death offers a promising approach to overcome apoptosis evasion in cancer treatment.
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