Beta-Lapachone

Beta-Lapachone is an inhibitor of DNA topoisomerase I [1].

Beta-Lapachone is found to inhibit the activity of topoisomerase I in a DNA unwinding assay. It inhibits the relaxation at 1μM. The potency of beta-Lapachone can be increased when pretreating topoisomerase I with beta-Lapachone for 5 min at 37°C. Beta-Lapachone is selective for topoisomerase I and shows no inhibition activity for topoisomerase II. Besides, beta-Lapachone is also proved to have no induction in topoisomerase I mediated DNA cleavage [1].

Beta-Lapachone has anti-tumor efficacy in a broad spectrum of human carcinoma cells. It induces cell death of AD2780s, HT-29, DLD, G480 and MCF-7 with IC50 values of 2μM, 5μM, 5μM, 4μM and 2μM, respectively. It is found that beta-Lapachone induces cell death of both apoptosis and necrosis through releasing cytochrome C. Beta-Lapachone is also reported to affect cell cycle. It induces primarily S-phase arrest in SW480 cells, late S- and G2/M-phase arrest in SW620 cells and early S-phase arrest in DLD1 cells [2, 3].

References:
[1] Li CJ, Averboukh L, Pardee AB. beta-Lapachone, a novel DNA topoisomerase I inhibitor with a mode of action different from camptothecin. J Biol Chem. 1993 Oct 25;268(30):22463-8.
[2] Li YZ, Li CJ, Pinto AV, Pardee AB. Release of mitochondrial cytochrome C in both apoptosis and necrosis induced by beta-lapachone in human carcinoma cells. Mol Med. 1999 Apr;5(4):232-9.
[3] Huang L, Pardee AB. beta-lapachone induces cell cycle arrest and apoptosis in human colon cancer cells. Mol Med. 1999 Nov;5(11):711-20.

Using a novel NQO1 bioactivatable drug, beta-lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer.[Pubmed:28346693]

J Surg Oncol. 2017 Jul;116(1):83-88.

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.

Selective Inhibitors of Human Liver Carboxylesterase Based on a beta-Lapachone Scaffold: Novel Reagents for Reaction Profiling.[Pubmed:28112927]

J Med Chem. 2017 Feb 23;60(4):1568-1579.

Carboxylesterases (CEs) are ubiquitous enzymes that are responsible for the metabolism of xenobiotics, including drugs such as irinotecan and oseltamivir. Inhibition of CEs significantly modulates the efficacy of such agents. We report here that Beta-Lapachone is a potent, reversible CE inhibitor with Ki values in the nanomolar range. A series of amino and phenoxy analogues have been synthesized, and although the former are very poor inhibitors, the latter compounds are highly effective in modulating CE activity. Our data demonstrate that tautomerism of the amino derivatives to the imino forms likely accounts for their loss in biological activity. A series of N-methylated amino derivatives, which are unable to undergo such tautomerism, were equal in potency to the phenoxy analogues and demonstrated selectivity for the liver enzyme hCE1. These specific inhibitors, which are active in cell culture models, will be exceptionally useful reagents for reaction profiling of esterified drugs in complex biological samples.

beta-Lapachone Inhibits Lung Metastasis of Colorectal Cancer by Inducing Apoptosis of CT26 Cells.[Pubmed:27923905]

Integr Cancer Ther. 2017 Dec;16(4):585-596.

BACKGROUND: Beta-Lapachone is a quinone-containing compound found in red lapacho ( Tabebuia impetiginosa, syn. T avellanedae) trees. Lapacho has been used in traditional medicine by several South and Central American indigenous people to treat various types of cancer. The purpose of this study was to investigate the antimetastatic properties of Beta-Lapachone and the underlying mechanisms using colon cancer cells. METHODS: This research used metastatic murine colon cancer cell lines, colon 26 (CT26) and colon 38 (MC38). A WST assay, annexin V assay, cell cycle analysis, wound healing assay, invasion assay, western blot analysis, and real-time reverse transcription-polymerase chain reaction were performed to examine the effects of Beta-Lapachone on metastatic phenotypes and molecular mechanisms. The effect of Beta-Lapachone on lung metastasis was assessed in a mouse experimental metastasis model. RESULTS: We found that the inhibition of proliferation of the colon cancer cell lines by Beta-Lapachone was due to the induction of apoptosis and cell cycle arrest. Beta-Lapachone induced the apoptosis of CT26 cells through caspase-3, -8, and -9 activation; poly(ADP-ribose) polymerase cleavage; and downregulation of the Bcl-2 family in a dose- and time-dependent manner. In addition, a low concentration of Beta-Lapachone decreased the cell migration and invasion by decreasing the expression of matrix metalloproteinases-2 and -9, and increased the expression of tissue inhibitors of metalloproteinases-1 and -2. Moreover, Beta-Lapachone treatment regulated the expression of epithelial-mesenchymal transition markers such as E- and N-cadherin, vimentin, beta-catenin, and Snail in CT26 cells. In the mouse experimental metastasis model, Beta-Lapachone significantly inhibited the lung metastasis of CT26 cells. CONCLUSIONS: Our results demonstrated the inhibitory effect of Beta-Lapachone on colorectal lung metastasis. This compound may be useful for developing therapeutic agents to treat metastatic cancer.

The inhibitory effect of beta-lapachone on RANKL-induced osteoclastogenesis.[Pubmed:27913299]

Biochem Biophys Res Commun. 2017 Jan 22;482(4):1073-1079.

Beta-Lapachone (beta-L) is a substrate of reduced nicotinamide adenine dinucleotide (NADH): quinone oxidoreductase 1 (NQO1). NQO1 reduces quinones to hydroquinones using NADH as an electron donor and consequently increases the intracellular NAD+/NADH ratio. The activation of NQO1 by beta-L has beneficial effects on several metabolic syndromes, such as obesity, hypertension, and renal injury. However, the effect of beta-L on bone metabolism remains unclear. Here, we show that beta-L might be a potent inhibitor of receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis. beta-L inhibited osteoclast formation in a dose-dependent manner and also reduced the expression of osteoclast differentiation marker genes, such as tartrate-resistant acid phosphatase (Acp5 or TRAP), cathepsin K (CtsK), the d2 isoform of vacuolar ATPase V0 domain (Atp6v0d2), osteoclast-associated receptor (Oscar), and dendritic cell-specific transmembrane protein (Dc-stamp). beta-L treatment of RANKL-induced osteoclastogenesis significantly increased the cellular NAD+/NADH ratio and resulted in the activation of 5' AMP-activated protein kinase (AMPK), a negative regulator of osteoclast differentiation. In addition, beta-L treatment led to significant suppression of the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC1beta), which can stimulate osteoclastogenesis. beta-L treatment downregulated c-Fos and nuclear factor of activated T-cells 1 (NFATc1), which are master transcription factors for osteoclastogenesis. Taken together, the results demonstrated that beta-L inhibits RANKL-induced osteoclastogenesis and could be considered a potent inhibitor of RANKL-mediated bone diseases, such as postmenopausal osteoporosis, rheumatoid arthritis, and periodontitis.

Suppression of tumor necrosis factor-activated nuclear transcription factor-kappaB, activator protein-1, c-Jun N-terminal kinase, and apoptosis by beta-lapachone.[Pubmed:10075082]

Biochem Pharmacol. 1999 Apr 1;57(7):763-74.

Beta-Lapachone, the product of a tree from South America, is known to exhibit various pharmacologic properties, the mechanisms of which are poorly understood. In the present report, we examined the effect of Beta-Lapachone on the tumor necrosis factor (TNF)-induced activation of the nuclear transcription factors NF-kappaB and activator protein-1 (AP-1) in human myeloid U937 cells. TNF-induced NF-kappaB activation, p65 translocation, IkappaBalpha degradation, and NF-kappaB-dependent reporter gene expression were inhibited in cells pretreated with Beta-Lapachone. Direct treatment of the p50-p65 heterodimer of NF-kappaB with Beta-Lapachone had no effect on its ability to bind to the DNA. Besides myeloid cells, Beta-Lapachone was also inhibitory in T-cells and epithelial cells. Beta-Lapachone also suppressed the activation of NF-kappaB by lipopolysaccharide, okadaic acid, and ceramide but had no significant effect on activation by H2O2 or phorbol myristate acetate, indicating that its action is selective. Beta-Lapachone also abolished TNF-induced activation of AP-1, c-Jun N-terminal kinase, and mitogen-activated protein kinase kinase (MAPKK or MEK). TNF-induced cytotoxicity and activation of caspase-3 were also abolished by Beta-Lapachone. Because reducing agents (dithiothreitol and N-acetylcysteine) reversed the effect of Beta-Lapachone, it suggests the role of a critical sulfhydryl group. Overall, our results identify NF-kappaB, AP-1, and apoptosis as novel targets for Beta-Lapachone, and this may explain some of its pharmacologic effects.

Activation of c-Jun NH2-terminal kinase and subsequent CPP32/Yama during topoisomerase inhibitor beta-lapachone-induced apoptosis through an oxidation-dependent pathway.[Pubmed:9927052]

Cancer Res. 1999 Jan 15;59(2):391-8.

Beta-Lapachone (beta-Lap) has been found to inhibit DNA topoisomerases (Topos) by a mechanism distinct from that of other commonly known Topo inhibitors. Here, we demonstrated a pronounced elevation of H2O2 and O2- in human leukemia HL-60 cells treated with beta-Lap. Treatment with other Topo poisons, such as camptothecin (CPT), Vbeta-16, and GL331, did not have the same effect. On the other hand, antioxidant vitamin C (Vit C) treatment effectively antagonized beta-Lap-induced apoptosis. This suggested that a reactive oxygen species (ROS)-related pathway was involved in beta-Lap-induced apoptosis program. We also found that c-Jun NH2-terminal kinase (JNK) but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 was persistently activated in apoptosis induced by beta-Lap. Overexpression of a dominant-negative mutant mitogen-activated protein kinase kinase kinase 1 (MEKK1-DN) or treatment with JNK-specific antisense oligonucleotide or Vit C all prevented beta-Lap-induced JNK activation and the subsequent apoptosis. Only the expression of MEKK1-DN, not Vit C treatment, blocked the JNK activity induced by CPT, Vbeta-16, or GL331. These results confirm again that ROS acts as a mediator for JNK activation during beta-Lap-induced apoptosis. Furthermore, we found that beta-Lap can stimulate CPP32/Yama activity, which was, however, markedly inhibited by the MEKK1-DN expression or Vit C treatment. Again, CPT-induced CPP32/Yama activation can be abolished by MEKK1-DN but not by Vit C treatment. Taken together, these results indicate that beta-Lap but not other Topo inhibitors triggers apoptosis signaling, i.e., JNK and subsequent CPP32/Yama activation are mediated by the generation of ROS.

Induction of apoptosis in MCF-7:WS8 breast cancer cells by beta-lapachone.[Pubmed:9581828]

Cancer Res. 1998 May 1;58(9):1876-85.

Beta-Lapachone (beta-lap) affects a number of enzymes in vitro, including type I topoisomerase (Topo I); however, its exact intracellular target(s) and mechanism of cell killing remain unknown. We compared the cytotoxic responses of MCF-7:WS8 (MCF-7) human breast cancer cells after 4-h pulses of beta-lap or camptothecin (CPT), a known Topo I poison. A direct correlation between loss of survival and apoptosis was seen after beta-lap treatment (LD50 = 2.5 microM). A concentration-dependent, transient sub-2 N preapoptotic cell population was observed at 4-8 h. Estrogen deprivation-induced synchronization and bromodeoxyuridine-labeling studies revealed an apoptotic exit point near the G1-S border. Apoptosis activated by beta-lap was closely correlated with cleavage of lamin B but not with increases in p53/p21 or decreases in bcl-2. Loss of hyperphosphorylated forms of the retinoblastoma protein was observed within 5 h, but cyclins A, B1, and E levels were unaltered for up to 72 h after 5 microM beta-lap. Topo I and Topo IIalpha levels decreased at > 24 h. Logarithmic-phase MCF-7 cells were not affected by < or = 1 microM beta-lap. In contrast, dramatic and irreversible G2-M arrest with no apoptosis was observed in MCF-7 cells treated with 1 microM CPT, monitored for 6-10 days posttreatment. MCF-7 cells treated with supralethal doses of CPT (5 microM) resulted in only approximately 20% apoptosis. No correlation between apoptosis and loss of survival was observed. MCF-7 cells exposed to > 5 microM CPT arrested at key cell cycle checkpoints (i.e., G1, S, and G2-M), with little or no movement for 6 days. Ten-fold increases in p53/p21 and 2-5-fold decreases in bcl-2, Topo I, Topo IIalpha, and cyclins A and B1, with no change in cyclin E, were observed. Temporal decreases in bcl-2 and cleavage of lamin B corresponded to the minimal apoptotic response observed. Beta-lap activated apoptosis without inducing p53/p21 or cell cycle arrest responses and killed MCF-7 cells solely by apoptosis. In contrast, concentration-dependent increases in nuclear p53/p21 and various cell cycle checkpoint arrests were seen in MCF-7 cells after CPT. Despite dramatic p53/p21 protein induction responses, CPT-treated MCF-7 cells showed low levels of apoptosis, possibly due to protective cell cycle checkpoints or the lack of specific CPT-activated apoptotic pathways in MCF-7 cells.

beta-Lapachone, a novel DNA topoisomerase I inhibitor with a mode of action different from camptothecin.[Pubmed:8226754]

J Biol Chem. 1993 Oct 25;268(30):22463-8.

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.

β-Lapachone (ARQ-501;NSC-26326) is a naturally occurring O-naphthoquinone, acts as a topoisomerase I inhibitor, and induces apoptosis by inhibiting cell cycle progression.

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