Novel Indole-based Tambjamine-Analogues Induce Apoptotic Lung Cancer Cell Death through p38 Mitogen-Activated Protein Kinase Activation

Abstract

Lung cancer has become the leading killer cancer worldwide, due to late diagnosis and lack of efficient anticancer drugs. We have recently described novel natural-derived tambjamine analogues that are potent anion transporters capable of disrupting cellular ion balance, inducing acidification of the cytosol and hyperpolarization of cellular plasma membranes. Although these tambjamine analogues were able to compromise cell survival, their molecular mechanism of action remains largely unknown. Herein we characterize the molecular cell responses induced by highly active indole-based tambjamine analogues treatment in lung cancer cells. Expression changes produced after compounds treatment comprised genes related to apoptosis, cell cycle, growth factors and its receptors, protein kinases and topoisomerases, among others. Dysregulation of and/survivin genes suggested the apoptotic pathway as the induced molecular cell death mechanism. In fact, activation of several proapoptotic markers (caspase-9, caspase-3, and PARP) and reversion of the cytotoxic effect upon treatment with an apoptosis inhibitor (Z-VAD-FMK) were observed. Moreover, members of the Bcl-2 protein family suffered changes after tambjamine analogues treatment, with a concomitant protein decrease towards the prosurvival members. Besides this, it was observed cellular accumulation of ROS upon compound treatment and an activation of the stress-kinase p38 MAPK route that, when inhibited, reverted the cytotoxic effect of the tambjamine analogues. Finally, a significant therapeutic effect of these compounds was observed in subcutaneous and orthotopic lung cancer mice models. Taken together, these results shed light on the mechanism of action of novel cytotoxic anionophores and demonstrate the therapeutic effects against lung cancer. .

Phototriggered Release of a Transmembrane Chloride Carrier from an o‐Nitrobenzyl‐Linked Procarrier

“…[5] Several biomimetic synthetic systems have been reported for transporting ions across the lipid membrane. [6] Recently,n atural and synthetic chloride transporters,f or example,p rodigiosin, [7] tambjamine, [8] ureas/thioureas, [9] calix [4]pyrroles, [10] squaramides, [11] and bis-sulfonamides, [12] that cause apoptosis-mediated cancer-cell death have been reported. These molecules function in the lipid membrane,r ather than binding to any specific genes or proteins/enzymes,a nd they perturb the intracellular chloride ion concentration to kill the cells.…”

Association of p38MAPK‐p53‐Fas aggregation in S‐allyl cysteine mediated regulation of hepatocarcinoma

“…Role of p38MAPK is evident by its close association in 2‐methoxyestradiol (2‐ME) induced apoptosis of prostate cancer; novel indole‐based Tambjamine‐analogues induced lung cancer cell death as well as vorinostat‐induced apoptosis in MDA‐MB‐231 human breast cancer cells . Current findings indicate that MKK6 induced p38MAPK cascade is involved in apoptotic pathway in parallel to inhibition in cell growth and proliferation .…”

From Seabed to Bedside: A Review on Promising Marine Anticancer Compounds

“…Moreover, compounds 1 and 2 reduced tumor burden in mice bearing subcutaneous and orthotopic DMS53 xenografts when injected i.p. at 6 mg/Kg, with compound 2 being the most potent with no obvious toxicity observed [94].…”

“…Recently indole-based analogs of Tambjamine were synthesized and were investigated in vivo in small-cell lung cancer DMS53 xenografts. Compounds 1 and 2 displayed IC 50 values below 10 µM [94]. It showed that apoptosis was the primary mechanism that resulted in cell death.…”