Beta Lapachone

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David A Boothman - One of the best experts on this subject based on the ideXlab platform.

  • Using DNA devices to track anticancer drug activity.
    Biosensors and Bioelectronics, 2016
    Co-Authors: Dimithree Kahanda, David A Boothman, Gaurab Chakrabarti, Marc A. Mcwilliams, Jason D. Slinker
    Abstract:

    It is beneficial to develop systems that reproduce complex reactions of biological systems while maintaining control over specific factors involved in such processes. We demonstrated a DNA device for following the repair of DNA damage produced by a redox-cycling anticancer drug, Beta-Lapachone (β-lap). These chips supported s-lap-induced biological redox cycle and tracked subsequent DNA damage repair activity with redox-modified DNA monolayers on gold. We observed drug-specific changes in square wave voltammetry from these chips at therapeutic s-lap concentrations of high statistical significance over drug-free control. We also demonstrated a high correlation of this change with the specific s-lap-induced redox cycle using rational controls. The concentration dependence of s-lap revealed significant signal changes at levels of high clinical significance as well as sensitivity to sub-lethal levels of s-lap. Catalase, an enzyme decomposing peroxide, was found to suppress DNA damage at a NQO1/catalase ratio found in healthy cells, but was clearly overcome at a higher NQO1/catalase ratio consistent with cancer cells. We found that it was necessary to reproduce key features of the cellular environment to observe this activity. Thus, this chip-based platform enabled tracking of s-lap-induced DNA damage repair when biological criteria were met, providing a unique synthetic platform for uncovering activity normally confined to inside cells.

  • abstract 3344 inhibiting base excision repair synergistically enhances Beta Lapachone mediated kiss of death for tumor selective therapy of pancreatic cancer
    Cancer Research, 2013
    Co-Authors: Long Shan Li, Xiumei Huang, Zachary R Moore, Ralph J Deberardinis, Rolf A Brekken, Stanton L Gerson, David A Boothman
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Pancreatic cancer will be the second leading cause of cancer-related deaths in the US by 2020, where 5-year survival is <6%. Current standard of care therapies offer little selectivity and high toxicity. Novel, tumor-selective approaches are desperately needed. Nearly 90% of pancreatic cancers have elevated levels (10- to 40-fold) NQO1 and we recently showed that Beta-Lapachone (Beta-lap) was efficacious against pancreatic cancers in an NQO1-dependent manner (Li et al., Clin. Cancer Res., 2011). Beta-Lap is reduced by NQO1 like most quinones, but unlike most, its hydroquinone form is unstable and spontaneously redox cycles in a futile manner where one mole of Beta-lap generates ∼120 moles of superoxide in two mins., inducing predominately DNA base and single strand break (SSB) damage. This results in PARP1 hyperactivation and programmed necrosis, killing NQO1+ cancer cells independent of: i, p53; ii, cell cycle; iii, all known oncogenic drivers; and iv, apoptotic/antiapoptotic gene expression (e.g., Bax, Bak, Bcl2). This ‘NQO1 bioactivatable drug’ is tumor-selective and a perfect candidate for improving efficacy of pancreatic cancer therapy. To improve its efficacy, we examined the synergistic effects of adding the AP site-modifying drug and base excision repair (BER) inhibitor, methoxyamine (MeOX), with Beta-lap against NQO1 over-expressing pancreatic cancer cells. MeOX + Beta-lap synergy resulted in: a, enhanced lethality of sublethal doses of Beta-lap, reducing the shoulder (Dq), increasing the lethality rate (Do), and inducing apoptosis (TUNEL+) in NQO1+, but not in NQO1-, MIA PaCa-2 cells; b, increased DNA lesion formation; c, dramatic losses in ATP levels, with little recovery; and d, dramatic suppression of glycolysis. These data strongly suggests that MeOX enhances PARP1 hyperactivation and synergistic cell killing of Beta-lap. Similar results were noted in shRNA-XRCC1 knockdown cells. Mechanistically, our data suggests that PARP1 detects MeOX-AP modified sites or SSBs, allowing PARP1 hyperactivation and synergistic cell death. Since MeOX is a nontoxic agent, and both agents are currently in clinical trials (i.e., Beta-lap as Arq761, Arqule, Boston, MA), combination therapies for the treatment of pancreatic, as well as other NQO1 over-expressing solid cancers could be rapidly developed. An AACR Innovator Award from the George and June Block Foundation to DAB supported this work. Citation Format: Xiuquan Luo, Longshan Li, Xiumei Huang, Lifen Cao, Zachary Moore, Ralph Deberardinis, Rolf Brekken, Stanton Gerson, Lili Liu, David A. Boothman. Inhibiting base excision repair synergistically enhances Beta-Lapachone-mediated ‘kiss of death’ for tumor-selective therapy of pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3344. doi:10.1158/1538-7445.AM2013-3344

  • Abstract 3344: Inhibiting base excision repair synergistically enhances Beta-Lapachone-mediated ‘kiss of death’ for tumor-selective therapy of pancreatic cancer.
    Cancer Research, 2013
    Co-Authors: Long Shan Li, Xiumei Huang, Zachary R Moore, Ralph J Deberardinis, Rolf A Brekken, Stanton L Gerson, David A Boothman
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Pancreatic cancer will be the second leading cause of cancer-related deaths in the US by 2020, where 5-year survival is

  • Abstract 5369: Prostate cancer radiosensitization through PARP-1 hyperactivation
    Cancer Research, 2011
    Co-Authors: Ying Dong, Long Shan Li, David A Boothman
    Abstract:

    Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The clinical experimental agent, Beta-Lapachone (Arq 501), can act as a potent radiosensitizer in vitro through an unknown mechanism. In this study, we analyzed the mechanism to determine whether Beta-Lapachone may warrant clinical evaluation as a radiosensitizer. Beta-Lapachone killed prostate cancer cells by NAD(P)H:quinone oxidoreductase 1 (NQO1) metabolic bioactivation, triggering a massive induction of reactive oxygen species (ROS), irreversible DNA single strand breaks (SSBs), PARP-1 hyperactivation, NAD+/ATP depletion, and µ-calpain-induced programmed necrosis. In combination with ionizing radiation (IR), Beta-Lapachone radiosensitized NQO1+ prostate cancer cells, under conditions where nontoxic doses of either agent alone achieved threshold levels of SSBs required for hyperactivation of PARP-1. Combination therapy significantly elevated SSBs, gamma-H2AX foci formation, and poly(ADP-ribosylation) of PARP-1, which were associated with ATP loss and induction of µ-calpain-induced programmed cell death. Radiosensitization by Beta-Lapachone was blocked by the NQO1 inhibitor, dicoumarol, or the PARP-1 inhibitor, DPQ. In a mouse xenograft model of prostate cancer, Beta-Lapachone synergized with IR to promote antitumor efficacy. NQO1 levels were elevated in ∼60% of human prostate tumors evaluated relative to adjacent normal tissue, where Beta-Lapachone might be efficacious alone or in combination with radiation. Our findings offer a rationale for clinical assessment of Beta-Lapachone (Arq501) as a radiosensitizer in prostate cancers that overexpress NQO1, offering a potentially synergistic targeting strategy to exploit PARP-1 hyperactivation. Since similar data have been found for all NQO1 endogenously over-expressing cancers, including nonsmall cell lung, pancreatic and breast cancer, this strategy should have a broad use for many cancers and in combination with many DNA damaging agents used for cancer therapy. This work was supported by NIH grant 2 R01 CA102792 to DAB Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5369. doi:10.1158/1538-7445.AM2011-5369

  • Exploiting Novel Calcium-Mediated Apoptotic Processes for the Treatment of Human Breast Cancers with Elevated Nqo1 Levels
    2008
    Co-Authors: Melissa S. Bentle, David A Boothman
    Abstract:

    Abstract : Beta-Lapachone (Beta-lap; a.k.a. ARQ 501) is currently in Phase II clinical trials for the treatment of pancreatic adenocarcinoma in combination with gemcitabine. Beta-Lap is a novel antitumor agent that is bio-activated by the two-electron oxidoreductase NAD(P)H quinone oxidoreductase-1 (NQO1) (E.C. 1.6.99.2). Since NQO1 is highly expressed in many human cancers (e.g. breast, lung, pancreatic, and prostate cancer) it is an attractive target for selective cancer chemotherapy by Beta-lap alone or in combination with IR (1-3). We previously reported that the initiation of Beta-lap-induced cell death is triggered by the NQO1-dependent oxidoreduction of Beta-lap (1). NQO1-mediated metabolism of Beta-lap results in a futile cycling event wherein Beta-lap is reduced to an unstable hydroquinone that reverts spontaneously back to its parent structure, using two molecules of oxygen (4). As a result, ROS are generated causing DNA damage, Beta-H2AX foci formation, poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, and subsequent loss of ATP and NAD+ (5). This loss of ATP and NAD+ was proposed to be the mechanism by which Beta-lap could enhance the sensitivities of a variety of chemotherapeutic therapies as well as IR (6). B-lap-induced cell death was unique in that PARP-1 and p53 were cleaved concomitant with -calpain activation, consistent with the fact that global caspase inhibitors had little effect on Beta-lap-induced proteolysis and lethality (1, 7). Interestingly, Beta-lap-mediated cell death exhibited classical features of apoptosis (e.g. DNA condensation, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells), but was not dependent on standard apoptotic mediators such as p53, Bax/Bak, or caspases (8).

Arthur B Pardee - One of the best experts on this subject based on the ideXlab platform.

  • potent induction of apoptosis by Beta Lapachone in human multiple myeloma cell lines and patient cells
    Molecular Medicine, 2000
    Co-Authors: Youzhi Li, Chiang J Li, Donghui Yu, Arthur B Pardee
    Abstract:

    BACKGROUND: Human multiple myeloma (MM) remains an incurable hematological malignancy. We have reported that Beta-Lapachone, a pure compound derived from a plant, can induce cell death in a variety of human carcinoma cells, including ovary, colon, lung, prostate, pancreas, and breast, suggesting a wide spectrum of anticancer activity. MATERIALS AND METHODS: We first studied antisurvival effects of Beta-Lapachone in human MM cells by colony formation assay. To determine whether the differential inhibition of colony formation occurs through antiproliferative activity, we performed MTT assays. The cytotoxicity of Beta-Lapachone on human peripheral blood mononuclear cells was also measured by MTT assay. To determine whether the cell death induced by Beta-Lapachone occurs through necrosis or apoptosis, we used the propidium iodide staining procedure to determine the sub-GI fraction, Annexin-V staining for externalization of phosphatidylserine, and fragmentation of cellular genomic DNA subjected to gel electrophoresis. To investigate the mechanism of anti-MM activity, we examined Bcl-2 expression, cytochrome C release, and poly (ADP ribose) polymerase cleavage by Western blot assay. RESULTS: We found that Beta-Lapachone (less than 4 microM) inhibits cell survival and proliferation by triggering cell death with characteristics of apoptosis in ARH-77, HS Sultan, and MM.1S cell lines, in freshly derived patient MM cells (MM.As), MM cell lines resistant to dexamethasone (MM.1R), doxorubicin (DOX.40), mitoxantrone (MR.20), and mephalan (LR5). Importantly, after treatment with Beta-Lapachone, we observed no apoptosis in peripheral blood mononuclear cells in either quiescent or proliferative states, freshly isolated from healthy donors. In Beta-Lapachone treated ARH-77, cytochrome C was released from mitochondria to cytosol, and poly (ADP ribose) polymerase was cleaved, signature events of apoptosis. Finally, the apoptosis induced by Beta-Lapachone in MM cells was not blocked by either interleukin-6 or Bcl-2, which confer multidrug resistance in MM. CONCLUSIONS: Our results suggest potential therapeutic application of Beta-Lapachone against MM, particularly to overcome drug resistance in relapsed patients.

  • potent inhibition of tumor survival in vivo by Beta Lapachone plus taxol combining drugs imposes different artificial checkpoints
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: Chiang J Li, Youzhi Li, Antonio Pinto, Arthur B Pardee
    Abstract:

    Ablation of tumor colonies was seen in a wide spectrum of human carcinoma cells in culture after treatment with the combination of β-Lapachone and taxol, two low molecular mass compounds. They synergistically induced death of cultured ovarian, breast, prostate, melanoma, lung, colon, and pancreatic cancer cells. This synergism is schedule dependent; namely, taxol must be added either simultaneously or after β-Lapachone. This combination therapy has unusually potent antitumor activity against human ovarian and prostate tumor prexenografted in mice. There is little host toxicity. Cells can commit to apoptosis at cell-cycle checkpoints, a mechanism that eliminates defective cells to ensure the integrity of the genome. We hypothesize that when cells are treated simultaneously with drugs activating more than one different cell-cycle checkpoint, the production of conflicting regulatory signaling molecules induces apoptosis in cancer cells. β-Lapachone causes cell-cycle delays in late G1 and S phase, and taxol arrests cells at G2/M. Cells treated with both drugs were delayed at multiple checkpoints before committing to apoptosis. Our findings suggest an avenue for developing anticancer therapy by exploiting apoptosis-prone “collisions” at cell-cycle checkpoints.

  • Beta Lapachone induces cell cycle arrest and apoptosis in human colon cancer cells
    Molecular Medicine, 1999
    Co-Authors: Lili Huang, Arthur B Pardee
    Abstract:

    Human colon cancers have a high frequency of p53 mutations, and cancer cells expressing mutant p53 tend to be resistant to current chemo- and radiation therapy. It is thus important to find therapeutic agents that can inhibit colon cancer cells with altered p53 status. β-Lapachone, a novel topoisomerase inhibitor, has been shown to induce cell death in human promyelocytic leukemia and prostate cancer cells through a p53-independent pathway. Here we examined the effects of β-Lapachone on human colon cancer cells. Several human colon cancer cell lines, SW480, SW620, and DLD1, with mutant or defective p53, were used. The antiproliferative effects of β-Lapachone were assessed by colony formation assays, cell cycle analysis, and apoptosis analysis, including annexin V staining and DNA laddering analysis. The effects on cell cycle and apoptosis regulatory proteins were examined by immunoblotting. All three cell lines, SW480, SW620, and DLD1, were sensitive to β-Lapachone, with an IC50 of 2 to 3 µM in colony formation assays, a finding similar to that previously reported for prostate cancer cells. However, these cells were arrested in different stages of S phase. At 24 hr post-treatment, β-Lapachone induced S-, late S/G2-, and early S-phase arrest in SW480, SW620, and DLD1 cells, respectively. The cell cycle alterations induced by β-Lapachone were congruous with changes in cell cycle regulatory proteins such as cyclin A, cyclin B1, cdc2, and cyclin D1. Moreover, β-Lapachone induced apoptosis, as demonstrated by annexin V staining, flow cytometric analysis of DNA content, and DNA laddering analysis. Furthermore, down-regulation of mutant p53 and induction of p27 in SW480 cells, and induction of proapoptotic protein Bax in DLD1 cells may be pertinent to the anti-proliferative and apoptotic effects of β-Lapachone on these cells. β-Lapachone induced cell cycle arrest and apoptosis in human colon cancer cells through a p53-independent pathway. For human colon cancers, which often contain p53 mutations, β-Lapachone may prove to be a promising anticancer agent that can target cancer cells, especially those with mutant p53.

  • release of mitochondrial cytochrome c in both apoptosis and necrosis induced by Beta Lapachone in human carcinoma cells
    Molecular Medicine, 1999
    Co-Authors: Youzhi Li, Chiang J Li, Antonio Ventura Pinto, Arthur B Pardee
    Abstract:

    There are two fundamental forms of cell death: apoptosis and necrosis. Molecular studies of cell death thus far favor a model in which apoptosis and necrosis share very few molecular regulators. It appears that apoptotic processes triggered by a variety of stimuli converge on the activation of a member of the caspase family, such as caspase 3, which leads to the execution of apoptosis. It has been suggested that blocking of caspase activation in an apoptotic process may divert cell death to a necrotic demise, suggesting that apoptosis and necrosis may share some upstream events. Activation of caspase is preceded by the release of mitochondrial cytochrome C. We first studied cell death induced by β-Lapachone by MTT and colony-formation assay. To determine whether the cell death induced by β-Lapachone occurs through necrosis or apoptosis, we used the PI staining procedure to determine the sub-G1 fraction and the Annexin-V staining for externalization of phophatidylserine. We next compared the release of mitochondrial cytochrome C in apoptosis and necrosis. Mitochondrial cytochrome C was determined by Western blot analysis. To investigate changes in mitochondria that resulted in cytochrome C release, the mitochondrial membrane potential (delta psi) was analyzed by the accumulation of rhodamine 123, a membrane-permeant cationic fluorescent dye. The activation of caspase in apoptosis and necrosis were measured by using a profluorescent substrate for caspase-like proteases, PhiPhiLuxG6D2. β-Lapachone induced cell death in a spectrum of human carcinoma cells, including nonproliferating cells. It induced apoptosis in human ovary, colon, and lung cancer cells, and necrotic cell death in four human breast cancer cell lines. Mitochondrial cytochrome C release was found in both apoptosis and necrosis. This cytochrome C release occurred shortly after β-Lapachone treatment when cells were fully viable by trypan blue exclusion and MTT assay, suggesting that cytochrome C release is an early event in β-Lapachone induced apoptosis as well as necrosis. The mitochondrial cytochrome C release induced by β-Lapachone is associated with a decrease in mitochondrial transmembrane potential (delta psi). There was activation of caspase 3 in apoptotic cell death, but not in necrotic cell death. This lack of activation of CPP 32 in human breast cancer cells is consistent with the necrotic cell death induced by β-Lapachone as determined by absence of sub-G1 fraction, externalization of phosphatidylserine. β-Lapachone induces either apoptotic or necrotic cell death in a variety of human carcinoma cells including ovary, colon, lung, prostate, and breast, suggesting a wide spectrum of anti-cancer activity in vitro. Both apoptotic and necrotic cell death induced by β-Lapachone are preceded by a rapid release of cytochrome C, followed by the activation of caspase 3 in apoptotic cell death but not in necrotic cell death. Our results suggest that β-Lapachone is a potential anti-cancer drug acting on the mitochondrial cytochrome C-caspase pathway, and that cytochrome C is involved in the early phase of necrosis.

  • Beta Lapachone a novel dna topoisomerase i inhibitor with a mode of action different from camptothecin
    Journal of Biological Chemistry, 1993
    Co-Authors: C J Li, Lidia Averboukh, Arthur B Pardee
    Abstract:

    Abstract Beta-Lapachone is a plant product that has been found to have many pharmacological effects. To date, very little is known about its biochemical target. In this study, we found that Beta-Lapachone inhibits the catalytic activity of topoisomerase I from calf thymus and human cells. But, unlike camptothecin, Beta-Lapachone does not stabilize the cleavable complex, indicating a different mechanism of action. Beta-Lapachone inhibits topoisomerase I-mediated DNA cleavage induced by camptothecin. Incubation of topoisomerase I with Beta-Lapachone before adding DNA substrate dramatically increases this inhibition. Incubation of topoisomerase I with DNA prior to Beta-Lapachone makes the enzyme refractory, and treatment of DNA with Beta-Lapachone before topoisomerase has no effect. These results suggest a direct interaction of Beta-Lapachone with topoisomerase I rather than DNA substrate. Beta-Lapachone does not inhibit binding of enzyme to DNA substrate. In cells, Beta-Lapachone itself does not induce a SDS-K(+)-precipitable complex, but it inhibits complex formation with camptothecin. We propose that the direct interaction of Beta-Lapachone with topoisomerase I does not affect the assembly of the enzyme-DNA complex but does inhibit the formation of cleavable complex.

Du Geon Moon - One of the best experts on this subject based on the ideXlab platform.

  • corpus cavernosal smooth muscle relaxation effect of a novel ampk activator Beta Lapachone
    The Journal of Sexual Medicine, 2011
    Co-Authors: Gi Ryang Kweon, Myoung Gyu Park, Kyeong-hoon Jeong, Du Geon Moon
    Abstract:

    INTRODUCTION: Adenosine monophosphate-activated protein kinase (AMPK) activation is suggested to relax smooth muscle by endothelial nitric oxide synthase (eNOS) phosphorylation. AIM: To assess the mechanism and effect of a novel AMPK activator, Beta-Lapachone, upon cavernosal smooth muscle relaxation and the therapeutic potential for erectile dysfunction. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with Beta-Lapachone. The lysates were blotted with specific antibodies for phosphorylated AMPK (p-AMPK) or phosphorylated eNOS (p-eNOS). The membranes were re-blotted for total AMP total eNOS, or Beta-actin. The eNOS activity was measured by the conversion of L-14C-arginine to L-14C-citrulline in HUVECs lysates. In a separated experiment, cavernosal strips from New Zealand white rabbits were harvested for organ bath study and the relaxation effect of Beta-Lapachone on phenylephrine-induced contracted strips was evaluated and compared with sodium nitroprusside, zaprinast, metformin, and aminoimidazole carboxamide ribonucleotide (AICAR). Methylene blue and L-NAME were used to assess the inhibition of cyclic guanosine monophosphate/nitric oxide pathway. Zinc-protoporphyrin-IX (ZnPP) was also used to investigate the contribution of mevalonate pathway. MAIN OUTCOME MEASURES: The expression of p-AMPK, p-eNOS, AMPK and eNOS induced by Beta-Lapachone in HUVECs study and the percent relaxation of cavernosal tissue in organ bath study. RESULTS: Beta-Lapachone clearly induced AMPK phosphorylation and, as a consequence, eNOS phosphorylation in HUVECs. Beta-Lapachone-induced upregulation of eNOS activity was also observed in HUVECs and steadily increased up to 1 hour. In organ bath study, Beta-Lapachone significantly relaxed the phenylephrine pretreated strips in a dose-dependent manner. This relaxation effect was not totally blocked by methylene blue or L-NAME. After removing endothelium, the relaxation was totally blocked by ZnPP. CONCLUSIONS: A novel AMPK activator, Beta-Lapachone has a strong relaxation effect on precontracted cavernosal smooth muscle strips in the rabbit. And phosphorylation of AMPK and eNOS strongly related to the action of Beta-Lapachone. Mevalonate pathway also might be considered as a suggestive mechanism.

Long Shan Li - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3344 inhibiting base excision repair synergistically enhances Beta Lapachone mediated kiss of death for tumor selective therapy of pancreatic cancer
    Cancer Research, 2013
    Co-Authors: Long Shan Li, Xiumei Huang, Zachary R Moore, Ralph J Deberardinis, Rolf A Brekken, Stanton L Gerson, David A Boothman
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Pancreatic cancer will be the second leading cause of cancer-related deaths in the US by 2020, where 5-year survival is <6%. Current standard of care therapies offer little selectivity and high toxicity. Novel, tumor-selective approaches are desperately needed. Nearly 90% of pancreatic cancers have elevated levels (10- to 40-fold) NQO1 and we recently showed that Beta-Lapachone (Beta-lap) was efficacious against pancreatic cancers in an NQO1-dependent manner (Li et al., Clin. Cancer Res., 2011). Beta-Lap is reduced by NQO1 like most quinones, but unlike most, its hydroquinone form is unstable and spontaneously redox cycles in a futile manner where one mole of Beta-lap generates ∼120 moles of superoxide in two mins., inducing predominately DNA base and single strand break (SSB) damage. This results in PARP1 hyperactivation and programmed necrosis, killing NQO1+ cancer cells independent of: i, p53; ii, cell cycle; iii, all known oncogenic drivers; and iv, apoptotic/antiapoptotic gene expression (e.g., Bax, Bak, Bcl2). This ‘NQO1 bioactivatable drug’ is tumor-selective and a perfect candidate for improving efficacy of pancreatic cancer therapy. To improve its efficacy, we examined the synergistic effects of adding the AP site-modifying drug and base excision repair (BER) inhibitor, methoxyamine (MeOX), with Beta-lap against NQO1 over-expressing pancreatic cancer cells. MeOX + Beta-lap synergy resulted in: a, enhanced lethality of sublethal doses of Beta-lap, reducing the shoulder (Dq), increasing the lethality rate (Do), and inducing apoptosis (TUNEL+) in NQO1+, but not in NQO1-, MIA PaCa-2 cells; b, increased DNA lesion formation; c, dramatic losses in ATP levels, with little recovery; and d, dramatic suppression of glycolysis. These data strongly suggests that MeOX enhances PARP1 hyperactivation and synergistic cell killing of Beta-lap. Similar results were noted in shRNA-XRCC1 knockdown cells. Mechanistically, our data suggests that PARP1 detects MeOX-AP modified sites or SSBs, allowing PARP1 hyperactivation and synergistic cell death. Since MeOX is a nontoxic agent, and both agents are currently in clinical trials (i.e., Beta-lap as Arq761, Arqule, Boston, MA), combination therapies for the treatment of pancreatic, as well as other NQO1 over-expressing solid cancers could be rapidly developed. An AACR Innovator Award from the George and June Block Foundation to DAB supported this work. Citation Format: Xiuquan Luo, Longshan Li, Xiumei Huang, Lifen Cao, Zachary Moore, Ralph Deberardinis, Rolf Brekken, Stanton Gerson, Lili Liu, David A. Boothman. Inhibiting base excision repair synergistically enhances Beta-Lapachone-mediated ‘kiss of death’ for tumor-selective therapy of pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3344. doi:10.1158/1538-7445.AM2013-3344

  • Abstract 3344: Inhibiting base excision repair synergistically enhances Beta-Lapachone-mediated ‘kiss of death’ for tumor-selective therapy of pancreatic cancer.
    Cancer Research, 2013
    Co-Authors: Long Shan Li, Xiumei Huang, Zachary R Moore, Ralph J Deberardinis, Rolf A Brekken, Stanton L Gerson, David A Boothman
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Pancreatic cancer will be the second leading cause of cancer-related deaths in the US by 2020, where 5-year survival is

  • Abstract 5369: Prostate cancer radiosensitization through PARP-1 hyperactivation
    Cancer Research, 2011
    Co-Authors: Ying Dong, Long Shan Li, David A Boothman
    Abstract:

    Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The clinical experimental agent, Beta-Lapachone (Arq 501), can act as a potent radiosensitizer in vitro through an unknown mechanism. In this study, we analyzed the mechanism to determine whether Beta-Lapachone may warrant clinical evaluation as a radiosensitizer. Beta-Lapachone killed prostate cancer cells by NAD(P)H:quinone oxidoreductase 1 (NQO1) metabolic bioactivation, triggering a massive induction of reactive oxygen species (ROS), irreversible DNA single strand breaks (SSBs), PARP-1 hyperactivation, NAD+/ATP depletion, and µ-calpain-induced programmed necrosis. In combination with ionizing radiation (IR), Beta-Lapachone radiosensitized NQO1+ prostate cancer cells, under conditions where nontoxic doses of either agent alone achieved threshold levels of SSBs required for hyperactivation of PARP-1. Combination therapy significantly elevated SSBs, gamma-H2AX foci formation, and poly(ADP-ribosylation) of PARP-1, which were associated with ATP loss and induction of µ-calpain-induced programmed cell death. Radiosensitization by Beta-Lapachone was blocked by the NQO1 inhibitor, dicoumarol, or the PARP-1 inhibitor, DPQ. In a mouse xenograft model of prostate cancer, Beta-Lapachone synergized with IR to promote antitumor efficacy. NQO1 levels were elevated in ∼60% of human prostate tumors evaluated relative to adjacent normal tissue, where Beta-Lapachone might be efficacious alone or in combination with radiation. Our findings offer a rationale for clinical assessment of Beta-Lapachone (Arq501) as a radiosensitizer in prostate cancers that overexpress NQO1, offering a potentially synergistic targeting strategy to exploit PARP-1 hyperactivation. Since similar data have been found for all NQO1 endogenously over-expressing cancers, including nonsmall cell lung, pancreatic and breast cancer, this strategy should have a broad use for many cancers and in combination with many DNA damaging agents used for cancer therapy. This work was supported by NIH grant 2 R01 CA102792 to DAB Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5369. doi:10.1158/1538-7445.AM2011-5369

Xiumei Huang - One of the best experts on this subject based on the ideXlab platform.

  • using a novel nqo1 bioactivatable drug Beta Lapachone arq761 to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer
    Journal of Surgical Oncology, 2017
    Co-Authors: Xiumei Huang, Ralph J Deberardinis, Molly A Silvers, David E Gerber, Joyce D Bolluyt, Venetia R Sarode, Farjana Fattah, Matthew E Merritt, Richard D Leff, Daniel Laheru
    Abstract:

    : Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor versus associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H2 O2 ) levels; normal tissues are spared by low NQO1 and high catalase expression. DNA damage created by ARQ761 in pancreatic cancer cells "hyperactivates" PARP1, causing metabolic catastrophe and NAD ± keresis cell death. NQO1: catalase levels (high in tumor, low in normal tissue) are an attractive therapeutic window to treat pancreatic cancer. Based on a growing body of literature, we are leading a clinical trial to evaluate the combination of ARQ761 and chemotherapy in patients with pancreatic cancer.

  • Using a novel NQO1 bioactivatable drug, BetaLapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer
    Journal of Surgical Oncology, 2017
    Co-Authors: Xiumei Huang, Ralph J Deberardinis, Molly A Silvers, David E Gerber, Joyce D Bolluyt, Venetia R Sarode, Farjana Fattah, Matthew E Merritt
    Abstract:

    : Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor versus associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H2 O2 ) levels; normal tissues are spared by low NQO1 and high catalase expression. DNA damage created by ARQ761 in pancreatic cancer cells "hyperactivates" PARP1, causing metabolic catastrophe and NAD ± keresis cell death. NQO1: catalase levels (high in tumor, low in normal tissue) are an attractive therapeutic window to treat pancreatic cancer. Based on a growing body of literature, we are leading a clinical trial to evaluate the combination of ARQ761 and chemotherapy in patients with pancreatic cancer.

  • abstract 3344 inhibiting base excision repair synergistically enhances Beta Lapachone mediated kiss of death for tumor selective therapy of pancreatic cancer
    Cancer Research, 2013
    Co-Authors: Long Shan Li, Xiumei Huang, Zachary R Moore, Ralph J Deberardinis, Rolf A Brekken, Stanton L Gerson, David A Boothman
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Pancreatic cancer will be the second leading cause of cancer-related deaths in the US by 2020, where 5-year survival is <6%. Current standard of care therapies offer little selectivity and high toxicity. Novel, tumor-selective approaches are desperately needed. Nearly 90% of pancreatic cancers have elevated levels (10- to 40-fold) NQO1 and we recently showed that Beta-Lapachone (Beta-lap) was efficacious against pancreatic cancers in an NQO1-dependent manner (Li et al., Clin. Cancer Res., 2011). Beta-Lap is reduced by NQO1 like most quinones, but unlike most, its hydroquinone form is unstable and spontaneously redox cycles in a futile manner where one mole of Beta-lap generates ∼120 moles of superoxide in two mins., inducing predominately DNA base and single strand break (SSB) damage. This results in PARP1 hyperactivation and programmed necrosis, killing NQO1+ cancer cells independent of: i, p53; ii, cell cycle; iii, all known oncogenic drivers; and iv, apoptotic/antiapoptotic gene expression (e.g., Bax, Bak, Bcl2). This ‘NQO1 bioactivatable drug’ is tumor-selective and a perfect candidate for improving efficacy of pancreatic cancer therapy. To improve its efficacy, we examined the synergistic effects of adding the AP site-modifying drug and base excision repair (BER) inhibitor, methoxyamine (MeOX), with Beta-lap against NQO1 over-expressing pancreatic cancer cells. MeOX + Beta-lap synergy resulted in: a, enhanced lethality of sublethal doses of Beta-lap, reducing the shoulder (Dq), increasing the lethality rate (Do), and inducing apoptosis (TUNEL+) in NQO1+, but not in NQO1-, MIA PaCa-2 cells; b, increased DNA lesion formation; c, dramatic losses in ATP levels, with little recovery; and d, dramatic suppression of glycolysis. These data strongly suggests that MeOX enhances PARP1 hyperactivation and synergistic cell killing of Beta-lap. Similar results were noted in shRNA-XRCC1 knockdown cells. Mechanistically, our data suggests that PARP1 detects MeOX-AP modified sites or SSBs, allowing PARP1 hyperactivation and synergistic cell death. Since MeOX is a nontoxic agent, and both agents are currently in clinical trials (i.e., Beta-lap as Arq761, Arqule, Boston, MA), combination therapies for the treatment of pancreatic, as well as other NQO1 over-expressing solid cancers could be rapidly developed. An AACR Innovator Award from the George and June Block Foundation to DAB supported this work. Citation Format: Xiuquan Luo, Longshan Li, Xiumei Huang, Lifen Cao, Zachary Moore, Ralph Deberardinis, Rolf Brekken, Stanton Gerson, Lili Liu, David A. Boothman. Inhibiting base excision repair synergistically enhances Beta-Lapachone-mediated ‘kiss of death’ for tumor-selective therapy of pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3344. doi:10.1158/1538-7445.AM2013-3344

  • Abstract 3344: Inhibiting base excision repair synergistically enhances Beta-Lapachone-mediated ‘kiss of death’ for tumor-selective therapy of pancreatic cancer.
    Cancer Research, 2013
    Co-Authors: Long Shan Li, Xiumei Huang, Zachary R Moore, Ralph J Deberardinis, Rolf A Brekken, Stanton L Gerson, David A Boothman
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Pancreatic cancer will be the second leading cause of cancer-related deaths in the US by 2020, where 5-year survival is