Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas

Abstract

Oral squamous cell carcinomas (OSCC) and esophageal squamous cell carcinomas (ESCC) exhibit a survival rate of less than 60% and 40%, respectively. Late-stage diagnosis and lack of effective treatment strategies make both OSCC and ESCC a significant health burden. Autophagy, a lysosome-dependent catabolic process, involves the degradation of intracellular components to maintain cell homeostasis. Targeting autophagy has been highlighted as a feasible therapeutic strategy with clinical utility in cancer treatment, although its associated regulatory mechanisms remain elusive. The detection of relevant biomarkers in biological fluids has been anticipated to facilitate early diagnosis and/or prognosis for these tumors. In this context, recent studies have indicated the presence of specific proteins and small RNAs, detectable in circulating plasma and serum, as biomarkers. Interestingly, the interplay between biomarkers (eg, exosomal microRNAs) and autophagic processes could be exploited in the quest for targeted and more effective therapies for OSCC and ESCC. In this review, we give an overview of the available biomarkers and innovative targeted therapeutic strategies, including the application of autophagy modulators in OSCC and ESCC.Additionally, we provide a viewpoint on the state of the art Tuhina Khan and Nicola Relitti contributed equally to this work. and on future therapeutic perspectives combining the early detection of relevant biomarkers with drug discovery for the treatment of OSCC and ESCC. K E Y W O R D S autophagy, autophagy modulators, biomarkers, esophageal squamous cell carcinoma, exosomes, oral squamous cell carcinoma, targeted therapy 1 | INTRODUCTION Oral squamous cell carcinoma (OSCC) is the predominant malignant neoplasm of the oral cavity followed by verrucous carcinoma, undifferentiated carcinoma, and small salivary adenocarcinoma. 1 Esophageal squamous cell carcinoma (ESCC) is the first histological type and accounts for 80% of cases of esophageal cancer. 2 OSCC and ESCC are indicated as one of the most common cancers by the International Union Against Cancer with an annual incidence of 275 000 and 456 000 cases worldwide, respectively. 3,4 The primary etiology in both OSCC and ESCC is attributed to the environmental factors (tobacco abuse, alcohol consumption), genetic factors (eg, mutations in enzymes), viral factors (human papilloma virus [HPV] infection), and/or the coexistence of these factors. Alcohol intake and tobacco use are responsible for at least 75% of these carcinomas. The underlying initiation and progression mechanisms of OSCC and ESCC are generally characterized by the accumulation of serial epigenetic and genetic alterations, which eventually lead to uncontrolled proliferation of the mutated cells, followed by vigorous cell division. 5,7 Early-stage OSCC detection displays an 80% survival rate at 5 years, while detection at advanced stage leads to survival rates ranging from 20% to 40%. 6 In ESCC, the 5-year survival rate for early-stage detection may reach 85%, whereas a dr...

Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma

“…The highest incidence of OSCC is observed in South 3 Asian countries and regions, such as India, Sri Lanka, and the south-central of China, which are caused by the high rates of cigarette smoking and areca nut use in these areas (5)(6)(7). Although the improvements in early diagnosis and surgical treatment over the past decades, OSCC usually progresses rapidly and presents high mortality rates, especially in patients with an advanced stage, and no targeted therapy is used in clinic for OSCC treatment currently (3,(6)(7)(8)(9). Thus, a better understanding of the mechanisms of OSCC oncogenesis and development of novel anti-tumor targets and drugs, are still the urgent demand for OSCC treatment.…”

Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma

“…The highest incidence of OSCC is observed in South Asian countries and regions, such as India, Sri Lanka, and the south-central of China, which are caused by the high rates of cigarette smoking and areca nut use in these areas [5][6][7]. Although the improvements in early diagnosis and surgical treatment over the past decades, OSCC usually progresses rapidly and presents high mortality rates, especially in patients with an advanced stage, and no targeted therapy is used in clinic for OSCC treatment currently [3,[6][7][8][9]. Thus, a better understanding of the mechanisms of OSCC oncogenesis and development of novel anti-tumor targets and drugs, are still the urgent demand for OSCC treatment.…”

A bioinformatics study of autophagy biomarkers associated with the prognosis of endometrial carcinoma

“…Autophagy is a mechanism that damages, degenerates or aging protein and organelles in cells are transported to the lysosome for digestion and degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors [6]. A growing body of research suggests that autophagy genes have a large potential to serve as promising markers in the diagnosis, prognosis, and personalized targeted therapies [7][8][9]. Autophagy mechanisms described in endometrial cancers, including the role of PI3K/AKT/mTOR, AMPK-mTOR, and p53 signaling pathways that trigger or inhibit this process, which may become a potential molecular target in clinical treatment methods [10].…”