Similar articles

Abstract: Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-‍;(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.

AAZ2可通过靶向PDK1介导线粒体依赖的凋亡

[1]AnwarS, ShamsiA, MohammadT, et al., 2021. Targeting pyruvate dehydrogenase kinase signaling in the development of effective cancer therapy. Biochim Biophys Acta Rev Cancer, 1876(1):188568.

[2]CuiQB, WangJQ, AssarafYG, et al., 2018. Modulating ROS to overcome multidrug resistance in cancer. Drug Resist Updat, 41:1-25.

[3]D'SouzaLC, MishraS, ChakrabortyA, et al., 2020. Oxidative stress and cancer development: are noncoding RNAs the missing links? Antioxid Redox Signal, 33(17):1209-1229.

[4]ElliottMA, FordSJ, PrasadE, et al., 2012. Pharmaceutical development of the novel arsenical based cancer therapeutic GSAO for Phase I clinical trial. Int J Pharm, 426(1-2):67-75.

[5]FattahiS, Amjadi-MohebF, TabaripourR, et al., 2020. PI3K/AKT/mTOR signaling in gastric cancer: epigenetics and beyond. Life Sci, 262:118513.

[6]García-GuerreroE, GötzR, DooseS, et al., 2021. Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab. Leukemia, 35:201-214.

[7]GuHF, HuangTH, ShenYC, et al., 2018. Reactive oxygen species-mediated tumor microenvironment transformation: the mechanism of radioresistant gastric cancer. Oxid Med Cell Longev, 2018:5801209.

[8]HarrisIS, DeNicolaGM, 2020. The complex interplay between antioxidants and ROS in cancer. Trends Cell Biol, 30(6):440-451.

[9]HayesJD, Dinkova-KostovaAT, TewKD, 2020. Oxidative stress in cancer. Cancer Cell, 38(2):167-197.

[10]JinL, KimEY, ChungTW, et al., 2020. Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity. Sci Rep, 10:21940.

[11]JoshiSS, BadgwellBD, 2021. Current treatment and recent progress in gastric cancer. CA Cancer J Clin, 71(3):264-279.

[12]LinJX, XieXS, WengXF, et al., 2019. UFM1 suppresses invasive activities of gastric cancer cells by attenuating the expression of PDK1 through PI3K/AKT signaling. J Exp Clin Cancer Res, 38:410.

[13]MissiroliS, PerroneM, GenoveseI, et al., 2020. Cancer metabolism and mitochondria: finding novel mechanisms to fight tumours. eBioMedicine, 59:102943.

[14]NerreterT, LetschertS, GötzR, et al., 2019. Super-resolution microscopy reveals ultra-low CD19 expression on myeloma cells that triggers elimination by CD19 CAR-T. Nat Commun, 10:3137.

[15]PaiS, YadavVK, KuoKT, et al., 2021. PDK1 inhibitor BX795 improves cisplatin and radio-efficacy in oral squamous cell carcinoma by downregulating the PDK1/CD47/Akt-mediated glycolysis signaling pathway. Int J Mol Sci, 22(21):11492.

[16]PerilloB, di DonatoM, PezoneA, et al., 2020. ROS in cancer therapy: the bright side of the moon. Exp Mol Med, 52(2):192-203.

[17]SanzMA, FenauxP, TallmanMS, et al., 2019. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood, 133(15):1630-1643.

[18]Škorja MilićN, DolinarK, MišK, et al., 2021. Suppression of pyruvate dehydrogenase kinase by dichloroacetate in cancer and skeletal muscle cells is isoform specific and partially independent of HIF-‍1α. Int J Mol Sci, 22(16):8610.

[19]SmythEC, NilssonM, GrabschHI, et al., 2020. Gastric cancer. Lancet, 396(10251):635-648.

[20]SradhanjaliS, TripathyD, RathS, et al., 2017. Overexpression of pyruvate dehydrogenase kinase 1 in retinoblastoma: a potential therapeutic opportunity for targeting vitreous seeds and hypoxic regions. PLoS ONE, 12(5):e0177744.

[21]SchneiderCA, RasbandWS, EliceiriKW, 2012. NIH Image to ImageJ: 25 years of image analysis. Nat Methods, 9(7):671-675.

[22]ShangMT, ZhouZW, KuangWB, et al., 2021. High-precision 3D drift correction with differential phase contrast images. Opt Express, 29(21):34641-34655.

[23]TataranniT, PiccoliC, 2019. Dichloroacetate (DCA) and cancer: an overview towards clinical applications. Oxid Med Cell Longev, 2019:8201079.

[24]TewariD, PatniP, BishayeeA, et al., 2022. Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: a novel therapeutic strategy. Semin Cancer Biol, 80:1-17.

[25]VelpulaKK, BhasinA, AsuthkarS, et al., 2013. Combined targeting of PDK1 and EGFR triggers regression of glioblastoma by reversing the Warburg effect. Cancer Res, 73(24):7277-7289.

[26]WadgaonkarP, ChenF, 2021. Connections between endoplasmic reticulum stress-associated unfolded protein response, mitochondria, and autophagy in arsenic-induced carcinogenesis. Semin Cancer Biol, 76:258-266.

[27]WangP, JinJM, LiangXH, et al., 2022. Helichrysetin inhibits gastric cancer growth by targeting c-Myc/PDHK1 axis-mediated energy metabolism reprogramming. Acta Pharmacol Sin, 43(6):1581-1593.

[28]WangQQ, JiangY, NaranmanduraH, 2020. Therapeutic strategy of arsenic trioxide in the fight against cancers and other diseases. Metallomics, 12(3):326-336.

[29]WangWP, DongXX, LiuY, et al., 2020. Itraconazole exerts anti-liver cancer potential through the Wnt, PI3K/AKT/mTOR, and ROS pathways. Biomed Pharmacother, 131:110661.

[30]WengMS, ChangJH, HungWY, et al., 2018. The interplay of reactive oxygen species and the epidermal growth factor receptor in tumor progression and drug resistance. J Exp Clin Cancer Res, 37:61.

[31]WuJ, HendersonC, FeunL, et al., 2010. Phase II study of darinaparsin in patients with advanced hepatocellular carcinoma. Invest New Drugs, 28(5):670-676.

[32]XuXH, WangHB, LiHY, et al., 2019. S-Dimethylarsino-glutathione (darinaparsin^®) targets histone H3.3, leading to TRAIL-induced apoptosis in leukemia cells. Chem Commun, 55(87):13120-13123.