LDHA Suppression Altering Metabolism Inhibits Tumor Progress by an Organic Arsenical

Abstract

Based on the potential therapeutic value in targeting metabolism for the treatment of cancer, an organic arsenical PDT-BIPA was fabricated, which exerted selective anti-cancer activity in vitro and in vivo via targeting lactate dehydrogenase A (LDHA) to remodel the metabolic pathway. In details, the precursor PDT-BIPA directly inhibited the function of LDHA and converted the glycolysis to oxidative phosphorylation causing ROS burst and mitochondrial dysfunction. PDT-BIPA also altered several gene expression, such as HIF-1α and C-myc, to support the metabolic remodeling. All these changes lead to caspase family-dependent cell apoptosis in vivo and in vitro without obvious side effect. Our results provided this organic arsenical precursor as a promising anticancer candidate and suggested metabolism as a target for cancer therapies.decisions through the regulation of metabolic enzymes [3]. Researchers showed immense interest of getting agents which could selectively eradicate cancer cells by altering metabolism [4]. However, few specific LDHA inhibitors complied with the envisaging results in vivo. Oxamate, a pyruvate analog that inhibits LDH activity by blocking the pyruvate binding site, is a weak inhibitor (IC 50~8 00 µM) and lacks selectivity. GNE-140 is a selective LDHA inhibitor of nano-molar potency but if it is removed from the medium, cells can proliferate even after 2 d of continuous inhibition which implies that sustained inhibition is needed for long-term cancer cell control [5]. Despite multiple efforts from researchers all around the world to discover potent inhibitors of LDHA, few viable inhibitors [1,[6][7][8][9][10] emerged except pioneering work of GSK and Genentech. Their cellular effects or in vivo activity did not meet the clinical demands in spite of the potent biochemical activity [7].Here, we report that reduction of LDHA by a synthesized organic arsenical causes bioenergetic and oxidative stress leading to cell apoptosis. The synthesized organic arsenical (PDT-BIPA) carrying the S-As-S displayed the best inhibition rates (IC 50/24 h = 0.55 ± 0.01 µM) for HL-60 cells among six cancer cell lines. PDT-BIPA can inhibit LDHA in HL-60 cells in a concentration-and time-dependent way leading to the burst of ROS and metabolic changes to suppress cancer cells and tumor in vitro and in vivo, respectively. Moreover, this compound manifested different inhibitory mechanism toward leukemia with our previous work [11,12].

A 13-Gene Metabolic Prognostic Signature Is Associated With Clinical and Immune Features in Stomach Adenocarcinoma

“…When the function of LDHA was inhibited, energy metabolism could convert glycolysis to oxidative phosphorylation, leading to an increase in ROS levels and mitochondrial dysfunction. The potential therapeutic value of targeting metabolite-driven genes for the treatment of cancer is breaking new ground ( 33 ). GSTM1 encodes glutathione S-transferase, and mutations in this gene have been linked to several biological processes, including drug susceptibility, oxidative stress, environmental toxicity, and tumorigenesis.…”

1,3-Benzodioxole Derivatives Improve the Anti-Tumor Efficiency of Arsenicals

“…The typical dosage of arsenic trioxide is about 5 mg/kg, which is far larger than our 1 or 1.5 mg/kg (considering the molecular concentration) [40]. In addition, the administration frequency was twice a week or every two days, in general [29]. Here, MAZ2 was administrated once a week and only administered twice overall to eliminate tumors.…”

“…1,3-Benzodioxole either kept its structure or derived to hydroxyl-substituted structures. The arsenicals were synthesized from As(V) precursors, which were mainly produced by ammonium thioglycolate reduction and 1,3-propanedithiol conjugation [19,29].…”

RAS-mediated tumor stress adaptation and the targeting opportunities it presents

“…These metabolic changes have important implications for cancer progression. For example, the inhibition of key metabolic enzymes that are upregulated in cancer, such as lactate dehydrogenase A (LDH-A) and the hexokinase isoform HK2, delays tumor progression ( Krushna et al, 2013 ; Liu et al, 2019 ). The glutaminase inhibitor CB-839, which targets an essential enzyme involved in glutamine metabolism, has shown promise in clinical trials, generating an objective response rate of 42% and a disease control rate of 100%, with 42% partial response and a 58% stable disease, when combined with the tyrosine kinase inhibitor cabozantinib in patients with metastatic renal cell cancer ( Meric-Bernstam et al, 2019 ; ).…”