Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer
Abstract:Current pharmacological treatments for lung cancer show very poor clinical outcomes, therefore, the development of novel anticancer agents with different mechanisms of action is urgently needed. Cancer cells have a reversed pH gradient compared to normal cells, which favors cancer progression by promoting proliferation, metabolic adaptation and evasion of apoptosis. In this regard, the use of ionophores to modulate intracellular pH appears as a promising new therapeutic strategy. Indeed, there is a growing bod… Show more
“…21 Following the study of the cytotoxicity of these compounds, a detailed study of the anti-cancer effect of tambjamine analogues 134 and 135 was carried out in several lung cancer cell lines by Pérez-Tomás and co-workers. 41 Treatment of A549 cells with these derivatives led to cytoplasmic vacuolization as a result of loss of mitochondrial potential and mitochondrial swelling. This could also trigger mitophagy (mitochondrial autophagy).…”
New approaches to the transmembrane transport of anions are discussed in this review. Advances in the design of small molecule anion carriers are reviewed in addition to advances in the design of synthetic anion channels. The application of anion transporters to the potential future treatment of disease is discussed in the context of recent findings on the selectivity of anion transporters.
“…21 Following the study of the cytotoxicity of these compounds, a detailed study of the anti-cancer effect of tambjamine analogues 134 and 135 was carried out in several lung cancer cell lines by Pérez-Tomás and co-workers. 41 Treatment of A549 cells with these derivatives led to cytoplasmic vacuolization as a result of loss of mitochondrial potential and mitochondrial swelling. This could also trigger mitophagy (mitochondrial autophagy).…”
New approaches to the transmembrane transport of anions are discussed in this review. Advances in the design of small molecule anion carriers are reviewed in addition to advances in the design of synthetic anion channels. The application of anion transporters to the potential future treatment of disease is discussed in the context of recent findings on the selectivity of anion transporters.
“…To investigate this further, Annexin-V was used as a marker with flow cytometry analysis to evaluate apoptosis in MDA-MB-231 cells after treatments with 2 (best transporter) and 6 (most potent) at their respective IC 50 values. It is known that synthetic transporters can disrupt ion homeostasis in cells and induce cell death via an apoptotic pathway 3 , 22 , 32 , 63 , 64 .…”
Section: Resultsmentioning
confidence: 99%
“…The disruption of autophagy by small molecule anion transporters results in the suppression of cell proliferation which is more pronounced in tumour cells 28 . A second family of recognised H + /Cl − cotransporters, the tambjamines 29 – 31 , have also been shown to induce lysosomal dysfunction 29 and autophagy blockage 32 as well as cancer cell death 3 . Figure 1 Schematic of prodigiosin (left) and perenosin (right) showing the chemical structures of these H + /Cl − cotransporters as free receptors and their respective HCl complexes.…”
Prodigiosin is one of the most potent anion transporters in lipid bilayer membranes reported to date. Inspired by the structure of this natural product, we have recently designed and synthesised a new class of H+/Cl− cotransporters named ‘perenosins’. Here we report a new library of indole-based perenosins and their anion transport properties. The new transporters demonstrated superior transmembrane transport efficiency when compared to other indole-based transporters, due to favourable encapsulating effects from the substituents on the perenosin backbone. Anion transport assays were used to determine the mechanism of chloride transport revealing that the compounds function as ‘strict’ HCl cotransporters. Cell viability studies showed that some compounds specifically trigger late-onset cell death after 72 h with a unique correlation to the position of alkyl chains on the perenosins. Further investigations of cell death mechanism showed a mixture of cell cycle arrest and apoptosis was responsible for the observed decrease in cell viability.
“…We have synthesized and studied synthetic analogs of these natural products, which proved to possess potent anticancer activity in vitro, including activity against cancer stem cells 12 . We are also studying in depth the molecular mechanisms responsible for this activity 13 . A series of these derivatives were submitted to the Target Drug Discovery Program, within the Open innovation drug discovery panel, operated by Lilly a .…”
Combining computational modeling, de novo compound synthesis, and in vitro and cellular assays, we have performed an inhibition study against the enhancer of zeste homolog 2 (EZH2) histone-lysine N-methyltransferase. This enzyme is an important catalytic component of the PRC2 complex whose alterations have been associated with different cancers. We introduce here several tambjamine-inspired derivatives with low micromolar in vitro activity that produce a significant decrease in histone 3 trimethylation levels in cancer cells. We demonstrate binding at the methyl transfer active site, showing, in addition, that the EZH2 isolated crystal structure is capable of being used in molecular screening studies. Altogether, this work provides a successful molecular model that will help in the identification of new specific EZH2 inhibitors and identify a novel class of tambjamine-derived EZH2 inhibitors with promising activities for their use in cancer treatment.
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