Targeting the ‘garbage-bin’ to fight cancer: HDAC6 inhibitor WT161 has an anti-tumor effect on osteosarcoma and synergistically interacts with 5-FU

Abstract

An imbalance between protein aggregation and protein degradation may induce “stress” in the functionality of the endoplasmic reticulum. There are quality control mechanisms to minimize misfolding and to eliminate misfolded proteins before aggregation becomes lethal for the cell. Proper protein folding and maturation is one of the crucial functions of the endoplasmic reticulum. Chaperones of the endoplasmic reticulum and folding enzymes guarantee correct conformational maturation of emerging secretory proteins. HDAC6 is a masterpiece coordinating the cell response to protein aggregate formation. The balance between HDAC6 and its partner Valosin-containing protein/p97 determines the fate of polyubiquitinated misfolded proteins. WT161 is a terrific, selective, and bioavailable HDAC6 inhibitor. WT161 selectively inhibits HDAC6 and adequately increases levels of acetylated α-tubulin. This compound induces accumulation of acetylated tubulin and cytotoxicity in multiple myeloma (MM) cells. In this Journal, Dr. Sun et al. identified that WT161 suppresses the cell growth of osteosarcoma cells. This discovery opens the door to future chemotherapeutic regimens of this bone neoplasm.

Role of Histone Deacetylase 6 and Histone Deacetylase 6 Inhibition in Colorectal Cancer

“…HDAC6 plays an active role in the response to environmental stress imposed by newly synthesized secretory proteins in the endoplasmic reticulum (ER) in order to eliminate misfolded proteins before protein aggregation becomes lethal for the cell [ 89 ]. In this sense, HDAC6 targets the 78 kDa glucose-regulated protein (GRP78) and Hsp70, the molecular chaperones that are involved in the unfolded protein response (UPR) that implies the regulation of proper folding, conformational maturation, assembly of proteins in ER, and control of the overall quality of proteins.…”

Engineered nanomaterials enhance drug delivery strategies for the treatment of osteosarcoma

“…In recent years, the treatment of OS has been continuously explored and studied. However, treatment of OS is still quite limited ( Sergi, 2021 ). Current conventional treatments for malignancy are chemotherapy, radiation therapy, and surgical resection ( Wu et al, 2022a ).…”

Mechanism and Role of Endoplasmic Reticulum Stress in Osteosarcoma

“…However, the therapeutic interventions for osteosarcoma are still quite limited. Conventional treatments included radiotherapy, chemotherapy, and surgical resection [ 7 ]. The treatments for osteosarcoma currently used in North America and Europe include neoadjuvant multidrug chemotherapy followed by surgical resection for controlling the local tumors at the site of the primary tumor, followed by focal treatment of metastatic sites [ 8 ].…”