Abstract
Oral squamous cell carcinoma (OSCC) is a kind of malignant tumors with low survival rate and prone to have early metastasis and recurrence. Cisplatin is an alkylating agent which induces DNA damage through the formation of cisplatin-DNA adducts, leading to cell cycle arrest and apoptosis. In the management of advanced OSCC, cisplatin-based chemotherapy or chemoradiotherapy has been considered as the first-line treatment. Unfortunately, only a portion of OSCC patients can benefit from cisplatin treatment, both inherent resistance and acquired resistance greatly limit the efficacy of cisplatin and even cause treatment failure. Herein, this review outline the underlying mechanisms of cisplatin resistance in OSCC from the aspects of DNA damage and repair, epigenetic regulation, transport processes, programmed cell death and tumor microenvironment. In addition, this review summarizes the strategies applicable to overcome cisplatin resistance, which can provide new ideas to improve the clinical therapeutic outcome of OSCC.
Highlights
Oral cancer is the sixth leading cause of global cancer-related deaths [1], with the most common type being oral squamous cell carcinoma (OSCC)
Reactive Oxygen Species (ROS) and cancerassociated fibroblasts (CAFs) have been reported to be associated with tumor progression in OSCC, and studies showed that these two factors contributed to cisplatin resistance through the induction of autophagy [63, 64]. These results have demonstrated that enhanced autophagy led to cisplatin resistance of OSCC, and inhibition of autophagy might be an effective method to reverse chemotherapy resistance
The benefits of the combined regime was not absolute, in another phase III clinical trial, the addition of cetuximab failed to improve PFS or overall survival (OS) in patients with stage III-IV OSCC receiving cisplatin and radiation therapy [166]. When it comes to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), regrettably, there was insufficient evidence showing the addition of EGFR-TKIs to standard therapies could provide overall therapeutic benefits
Summary
Oral cancer is the sixth leading cause of global cancer-related deaths [1], with the most common type being oral squamous cell carcinoma (OSCC). In a large-scale randomized clinical trial, a treatment regimen of postoperative radiotherapy combined with cisplatin chemotherapy significantly reduced local and regional recurrences and prolonged disease-free survival (DFS) in patients with advanced OSCC [11]. Considering the side effects and chemoresistance of cisplatin, researchers have developed thousands of cisplatin analogues [13], but only carboplatin and oxaliplatin are currently approved for clinical use These platinum-based agents, such as carboplatin, are less effective than cisplatin at the same dose, they reduce side effects to some extent [14]. A phase III clinical trial conducted in Sweden reported that cetuximab plus radiotherapy (RT) produced an overall toxicity comparable to cisplatin plus RT in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC), but showed inferiority in terms of local tumor control and treatment prognosis [15].
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