The marine natural product mimic MPM-1 is cytolytic and induces DAMP release from human cancer cell lines

Abstract

Bioprospecting contributes to the discovery of new molecules with anticancer properties. Compounds with cytolytic activity and the ability to induce immunogenic cell death can be administered as intratumoral injections with the aim to activate anti-tumor immune responses by causing the release of tumor antigens as well as damage-associated molecular patterns (DAMPs) from dying cancer cells. In the present study, we report the cytolytic and DAMP-releasing effects of a new natural product mimic termed MPM-1 that was inspired by the marine Eusynstyelamides . We found that MPM-1 rapidly killed cancer cells in vitro by inducing a necrosis-like death, which was accompanied by lysosomal swelling and perturbation of autophagy in HSC-3 (human oral squamous cell carcinoma) cells. MPM-1 also induced release of the DAMPs adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1) from Ramos (B-cell lymphoma) and HSC-3 cells, as well as cell surface expression of calreticulin in HSC-3 cells. This indicates that MPM-1 has the ability to induce immunogenic cell death, further suggesting that it may have potential as a novel anticancer compound.

Amphipathic barbiturates as marine product mimics with cytolytic and immunogenic effects on head and neck squamous cell carcinoma cell lines

“…Based on the structure of the previously reported marine natural product mimic MPM-1 ( von Hofsten et al, 2022 ), a panel of nine structurally related amphipathic barbiturates was developed. All compounds share the same barbiturate scaffold and lipophilic groups that are present in MPM-1 ( Figure 1 ).…”

“…Starting from dialkylated barbituric acid 1, all MPMs were synthesized based on modified procedures previously developed in our group ( Scheme 1 ) ( Langer et al, 2022 ; von Hofsten et al, 2022 ). N,N′-Dialkylation of substituted barbituric acid 1 was easily achieved under standard Mitsunobu conditions, employing diisopropyl azodicarboxylate (DIAD), triphenylphosphine (PPh3) and an aliphatic N-Boc protected amino alcohol of choice in anhydrous dichloromethane (DCM) ( Scheme 1 , upper pathway).…”

“…Detection of HMGB1 in the supernatant of MPM treated HSC-3 and UT-SCC-24A cells was performed as previously described ( von Hofsten et al, 2022 ). Briefly, HSC-3 and UT-SCC-24A cells were seeded, 100,000 cells/well in 12-well plates and left to adhere overnight.…”

“…We have previously reported on the cytolytic marine natural product mimic MPM-1 ( von Hofsten et al, 2022 ). MPM-1 is a simplified mimic of the natural product eusynstyelamide D , which has been isolated from an arctic bryozoan ( Tadesse et al, 2011 ).…”

“…In addition, both eusynstyelamide D and MPM-1 contain two cationic and two lipophilic groups, which makes these compounds amphipathic. Our previous study suggested that MPM-1 was able to induce immunogenic cell death in the HNSCC cell line HSC-3 ( von Hofsten et al, 2022 ). In the present study, we explore the anti-cancer and immunogenic effects of an extended panel of compounds which are structurally related to MPM-1.…”