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David A Boothman – 1st expert on this subject based on the ideXlab platform
Using DNA devices to track anticancer drug activity.Biosensors and Bioelectronics, 2016Co-Authors: Dimithree Kahanda, David A Boothman, Gaurab Chakrabarti, Marc A. Mcwilliams, Jason D. SlinkerAbstract:
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 cancerCancer Research, 2013Co-Authors: Long Shan Li, Xiumei Huang, Zachary R Moore, Ralph J Deberardinis, Rolf A Brekken, Stanton L Gerson, David A BoothmanAbstract:
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, 2013Co-Authors: Long Shan Li, Xiumei Huang, Zachary R Moore, Ralph J Deberardinis, Rolf A Brekken, Stanton L Gerson, David A BoothmanAbstract:
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
Arthur B Pardee – 2nd expert on this subject based on the ideXlab platform
potent induction of apoptosis by Beta Lapachone in human multiple myeloma cell lines and patient cellsMolecular Medicine, 2000Co-Authors: Youzhi Li, Chiang J Li, Donghui Yu, Arthur B PardeeAbstract:
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 checkpointsProceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Chiang J Li, Youzhi Li, Antonio Pinto, Arthur B PardeeAbstract:
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 cellsMolecular Medicine, 1999Co-Authors: Lili Huang, Arthur B PardeeAbstract:
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.
Du Geon Moon – 3rd expert on this subject based on the ideXlab platform
corpus cavernosal smooth muscle relaxation effect of a novel ampk activator Beta LapachoneThe Journal of Sexual Medicine, 2011Co-Authors: Gi Ryang Kweon, Myoung Gyu Park, Kyeong-hoon Jeong, Du Geon MoonAbstract:
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.