Low-molecular-weight polyphenol promotes cell sensitivity to cisplatin and alleviates cancer-related muscle atrophy via NF-κB suppression in oral squamous cell carcinoma

Abstract

Objective

Drug resistance and subsequent adverse effects, such as cancer cachexia, limit the clinical use of cisplatin. Oligonol® (Olg), a low-molecular-weight polyphenol, exhibits NF-κB inhibitory properties. NF-κB activation has been implicated in cisplatin resistance of cancer cells and skeletal muscle wasting. Therefore, we hypothesized that combined cisplatin and Olg could overcome chemoresistance and reduce muscle atrophy.

Methods

To investigate the efficiency of Olg, oral squamous cell carcinoma (OSCC) cells were used for chemosensitivity, and human skeletal muscle myoblast (HSkMC) was used for muscle atrophy. HSkMCs treated with OSCC cell-derived conditioned medium were used to examine the role of Olg in muscle atrophy mediated by the tumor inflammatory microenvironment.

Results

Olg exerted little effect on the viability of OSCC cells by promoting apoptotic cell death. However, it exhibited excellent capability to enhance the sensitivity of OSCC cells to cisplatin and overcome the acquired cisplatin resistance of OSCC. We revealed that NF-κB signaling contributes to cisplatin resistance in OSCC cells, whereas Olg enhances cell sensitivity to cisplatin by NF-κB suppression. Conversely, Olg contributes to a positive protein turnover and alleviates cisplatin-induced muscle atrophy by regulating Akt/mTOR/p70S6K and NF-κB/MuRF1 pathway. Olg represses TNF-α and interleukin 6 driven from OSCC cells and alleviates muscle atrophy mediated by the tumor inflammatory microenvironment.

Conclusions

Olg enhanced cisplatin chemosensitivity and reduced its adverse effects on skeletal muscle, suggesting its potential as a chemosensitizing agent for cisplatin. Further animal and clinical studies are required to validate these findings.