Novel Siglec-15-Sia axis inhibitor leads to colorectal cancer cell death by targeting miR-6715b-3p and oncogenes

Abstract

Siglecs are well known immunotherapeutic targets in cancer. Current checkpoint inhibitors have exhibited limited efficacy, prompting a need for novel therapeutics for targets such as Siglec-15. Presently, small molecule inhibitors targeting Siglec-15 are not explored alongside characterised regulatory mechanisms involving microRNAs in CRC progression. Therefore, a small molecule inhibitor to target Siglec-15 was elucidated in vitro and microRNA mediated inhibitor effects were investigated. Our research findings demonstrated that the SHG-8 molecule exerted significant cytotoxicity on cell viability, migration, and colony formation, with an IC50 value of approximately 20µM. SHG-8 exposure induced late apoptosis in vitro in SW480 CRC cells. Notably, miR-6715b-3p was the most upregulated miRNA in high-throughput sequencing, which was also validated via RT-qPCR. MiR-6715b-3p may regulate PTTG1IP, a potential oncogene which was validated via RT-qPCR and in silico analysis. Additionally, molecular docking studies revealed SHG-8 interactions with the Siglec-15 binding pocket with the binding affinity of -5.4 kcal/mol, highlighting its role as a small molecule inhibitor. Importantly, Siglec-15 and PD-L1 are expressed on mutually exclusive cancer cell populations, suggesting the potential for combination therapies with PD-L1 antagonists.

MicroRNA-Dependent Mechanisms Underlying the Function of a β-Amino Carbonyl Compound in Glioblastoma Cells

“…Beta-amino carbonyl derivatives have demonstrated promising potential in medicinal chemistry, drug development, and cancer therapy owing to their diverse biological activities and capacity to trigger apoptosis in cancerous cells. , This research incorporated an eco-friendly approach in an efficient, simple, and green catalytic process to produce SHG-8, aiming to demonstrate its in vitro cytotoxic effects on GB cell models.…”

“…Similar cytotoxic effects were previously observed with several β-AC compounds on human prostate cancer cells and colorectal cancer cells. 20 , 21 Currently, the most effective drug against gliomas is the chemotherapeutic agent TMZ. Combining chemotherapy with TMZ and radiotherapy is considered a gold standard therapeutic approach incorporated in the treatment regimens of GB patients with surgical tumor excision.…”

Unveiling the hub genes in the SIGLECs family in colon adenocarcinoma with machine learning

“…A large amount of evidence suggests that SIGLECs receptors hold promise as novel immune checkpoints and attractive targets for cancer immunotherapy ( Lim et al, 2021 ; Stanczak et al, 2023 ). Research suggests that combining SIGLEC15 with PD-L1 antagonists holds promise for treating colorectal cancer ( Ahmad et al, 2023 ). SIGLEC7 is implicated in modulating the immune response to Fusobacterium nucleatum in colorectal cancer ( Lamprinaki et al, 2021 ).…”

Potential of covalently linked tamoxifen hybrids for cancer treatment: recent update

“…31,32 Several reviews, including our recently published one discussing the significance of molecular hybrids in cancer treatment, are available in the literature. 18,33–37 The pharmacological relevance of hybrids and our experience in the field of cancer 38–43 and tamoxifen 1,44 motivated us to compile the review on tamoxifen hybrids and discuss their application in cancer treatment. This review compiles the recently reported covalently linked organometallic, fluorescent, photocaged, nanoparticle, and novel ligand-based tamoxifen hybrids and discusses their design strategies, chemical structure, and pharmacological profile.…”