β-Lapachone is an ortho-naphthoquinone natural product, promoting several biological effects, such as anti-inflammatory, antibacterial, and anti-Trypanosoma, and β-Lapachone can inhibit topoisomerase I and induce NAD(P)H: quinone oxidoreductase 1[1-3].
In vitro, after colon cancer cells SW480 cells were transiently exposed to β-Lapachone (2.5 or 5µM) for 4h, β-Lapachone induced primarily S-phase arrest in SW480 cells in a concentration-dependent manner[4]. Treatment of human hepatocellular carcinoma SK-Hep1 cells with different concentrations of β-Lapachone (1, 2, 4μM) for 18h showed that β-Lapachone increased the morphological appearance of dying cells in a dose-dependent manner, and cell viability was decreased in β-Lapachone-treated cells; furthermore, β-Lapachone also increased propidium iodide (PI) uptake (loss of plasma membrane integrity) in a dose-dependent manner[5].
In vivo, male Balb/c mice fed a diet containing β-Lapachone (0.066%) for 2 weeks before cisplatin injection (18mg/kg; i.p.), β-Lapachone markedly decreased cisplatin-induced renal cell apoptosis and DNA double-strand breaks (DSBs) formation, which was accompanied by enhanced basal expression of SIRTuin1, and the β-Lapachone + cisplatin group showed the highest Mre11-Rad50-Nbs1 (MRN) complex expression[6]. Log-phase A549 cells were injected subcutaneously into the flanks of athymic nude mice, followed by β-Lapachone (30mg/kg) injection through the tail vein, and β-Lapachone demonstrated potent in vivo antitumor activity with Tumor growth inhibition (TGI) = 70.1% and tumor proliferation rate (T/C) = 29.5%[7].
References:
[1] Gong Q, Hu J, Wang P, et al. A comprehensive review on β-lapachone: Mechanisms, structural modifications, and therapeutic potentials. Eur J Med Chem. 2021;210:112962.
[2] Ferraz da Costa DC, Pereira Rangel L, Martins-Dinis MMDDC, et al. Anticancer Potential of Resveratrol, β-Lapachone and Their Analogues. Molecules. 2020;25(4):893.
[3] Gomes CL, de Albuquerque Wanderley Sales V, Gomes de Melo C, et al. Beta-lapachone: Natural occurrence, physicochemical properties, biological activities, toxicity and synthesis. Phytochemistry. 2021;186:112713.
[4] Huang L, Pardee AB. beta-lapachone induces cell cycle arrest and apoptosis in human colon cancer cells. Mol Med. 1999;5(11):711-720.
[5] Park EJ, Min KJ, Lee TJ, Yoo YH, Kim YS, Kwon TK. β-Lapachone induces programmed necrosis through the RIP1-PARP-AIF-dependent pathway in human hepatocellular carcinoma SK-Hep1 cells. Cell Death Dis. 2014;5(5):e1230.
[6] Kim TW, Kim YJ, Kim HT, et al. β-Lapachone enhances Mre11-Rad50-Nbs1 complex expression in cisplatin-induced nephrotoxicity. Pharmacol Rep. 2016;68(1):27-31.
[7] Li X, Bian J, Wang N, et al. Novel naphtho[2,1-d]oxazole-4,5-diones as NQO1 substrates with improved aqueous solubility: Design, synthesis, and in vivo antitumor evaluation. Bioorg Med Chem. 2016;24(5):1006-1013.
β-Lapachone是一种邻萘醌天然产物，具有抗炎、抗菌及抗锥虫等多种生物活性，且能抑制拓扑异构酶I并诱导NAD(P)H:醌氧化还原酶1[1-3]。
在体外，将结肠癌细胞SW480短暂暴露于β-Lapachone(2.5或5µM)4小时后，β-Lapachone以浓度依赖性方式主要诱导SW480细胞发生S期阻滞[4]。采用不同浓度β-Lapachone (1、2、4μM)处理人肝细胞癌SK-Hep1细胞18小时的结果显示，β-Lapachone以剂量依赖性方式增加死亡细胞的形态学变化，β-Lapachone处理组细胞活力下降；此外，β-Lapachone亦以剂量依赖性方式增加碘化丙啶(PI)摄取(质膜完整性丧失)[5]。
在体内，雄性Balb/c小鼠于顺铂注射(18mg/kg；腹腔注射)前2周开始饲喂含β-Lapachone (0.066%)的饲料，β-Lapachone显著减少顺铂诱导的肾细胞凋亡和DNA双链断裂(DSBs)形成，伴随SIRTuin1基础表达上调，且β-Lapachone加顺铂组Mre11-Rad50-Nbs1(MRN)复合物表达最高[6]。将处于对数生长期的A549细胞皮下接种于无胸腺裸鼠侧腹，随后经尾静脉注射β-Lapachone (30mg/kg)，β-Lapachone表现出强效的体内抗肿瘤活性，肿瘤生长抑制率(TGI)=70.1%，肿瘤增殖率(T/C)=29.5%[7]。