GSDMD-dependent pyroptotic induction by a multivalent CXCR4-targeted nanotoxin blocks colorectal cancer metastases

Abstract

Colorectal cancer (CRC) remains the third cause of cancer-related mortality in Western countries, metastases are the main cause of death. CRC treatment remains limited by systemic toxicity and chemotherapy resistance. Therefore, nanoparticle-mediated delivery of cytotoxic agents selectively to cancer cells represents an efficient strategy to increase the therapeutic index and overcome drug resistance. We have developed the T22-PE24-H6 therapeutic protein-only nanoparticle that incorporates the exotoxin A from Pseudomonas aeruginosa to selectively target CRC cells because of its multivalent ligand display that triggers a high selectivity interaction with the CXCR4 receptor overexpressed on the surface of CRC stem cells. We here observed a CXCR4-dependent cytotoxic effect for T22-PE24-H6, which was not mediated by apoptosis, but instead capable of inducing a time-dependent and sequential activation of pyroptotic markers in CRC cells in vitro . Next, we demonstrated that repeated doses of T22-PE24-H6 inhibit tumor growth in a subcutaneous CXCR4 + CRC model, also through pyroptotic activation. Most importantly, this nanoparticle also blocked the development of lymphatic and hematogenous metastases, in a highly aggressive CXCR4 + SW1417 orthotopic CRC model, in the absence of systemic toxicity. This targeted drug delivery approach supports for the first time the clinical relevance of inducing GSDMD-dependent pyroptosis, a cell death mechanism alternative to apoptosis, in CRC models, leading to the selective elimination of CXCR4 + cancer stem cells, which are associated with resistance, metastases and anti-apoptotic upregulation.

Therapeutic properties, biological effects, antiliver cancer, and anticolon cancer effects of some natural compounds: A biochemical approach

“…The surface receptors with high expression in the mentioned cell lines were also evaluated using molecular docking. CD44 (PDB ID: 4PZ3) [ 31 ] was chosen for SNU‐C1, [ 32 ] endothelin receptor (PDB ID: 5 × 93) [ 33 ] was selected for SW48, [ 34 ] EGFR (PDB ID: 5WB7) [ 35 ] was chosen for RKO, [ 36 ] CD47 (PDB ID: 2JJS) [ 37 ] was chosen for COLO‐205, [ 38 ] CXCR4 (PDB ID: 3ODU) [ 39 ] was selected for SW1417, [ 40 ] HER2 (PDB ID: 1N8Z) [ 41 ] was chosen LS411N, [ 42 ] and folate receptor (PDB ID: 4LRH) was chosen for HEPG2. [ 43 ] The chemical activities of aromadendrin, artepillin C, bavachin, and bavachinin were estimated against these enzymes and proteins.…”

Pyroptosis and inflammasomes in cancer and inflammation

“…A nanoparticle‐based approach known as T22‐PE24‐H6 and T22‐DITOX‐H6 was created by the researchers. It targets colorectal cancer cells, inhibits tumor growth, and blocks lymphatic and hematogenous metastasis by triggering pyroptotic activation 182,183 . Zhang and coworkers 184 combine DAC with chemotherapeutic nano drugs to predemethylate and upregulate the GSDME in colon adenocarcinoma cells.…”

Chemokines and nanomaterials: interaction for useful immune-applications

“…Among the non-chemokine CXCR4-binding peptides, T22 is the most successful and it is frequently used to target diverse cancer cells over-expressing the receptor [59][60][61][62][63][64][65][66][67][68]. For instance, the release of doxorubicin in B cells from non-Hodgkin's lymphoma has been enhanced by capping mesoporous SiO 2 NPs with a derivative of the T22 peptide [60].…”