Oral cancer is a major public health issue as it is the sixth leading cause of cancer-related deaths worldwide (Sung et al., 2021). The most common type of oral cancer is oral squamous cell carcinoma (OSCC), which is a major cause of morbidity and mortality in patients with head and neck cancers (Gharat et al., 2016). Tongue squamous cell carcinoma (TSCC) is one of the most common OSCCs, accounting for 25–40 % of all cases. It is considered an aggressive form of OSCC because it is frequently associated with lymph node metastases and low survival rates (Ion Ciucă Mărăşescu et al., 2018).

Cisplatin (CP) is the most potent and widely used chemotherapeutic agent for patients with TSCC (Xue, Pan, Huang et al., 2020a). The antitumor activity of CP is attributed to its ability to induce cytotoxicity by forming adducts with genomic DNA, which directly damages DNA and inhibits DNA replication, thereby arresting the cell cycle and eventually leading to cell death (Sancho-Martínez et al., 2012). Unfortunately, CP may cause a variety of side effects in normal tissues, including neurotoxicity and/or renal toxicity, bone marrow suppression, allergic reactions, decreased immunity to infections, gastrointestinal disorders, hemorrhage, and hearing loss, particularly in younger patients (Dasari and Tchounwou, 2014, Florea and Büsselberg, 2011). Furthermore, chemoresistance has limited CP’s efficacy in cancer treatment. Cancer cells are no longer responsive to CP and can upregulate molecular pathways to induce drug resistance, resulting in continued tumour growth and metastatic spread (Shriwas et al., 2020). Therefore, a novel therapeutic strategy to reverse chemoresistance and enhance the anticancer effect of CP while minimizing its side effects is required (Garavaglia et al., 2016).

The prevention of cancer by natural constituents is a new strategy known as cancer chemoprevention, which has a high efficacy in controlling cancer development. Grape seed oil (GSO) is a type of vegetable edible oil derived from grape seeds. Due to its high levels of hydrophilic constituents such as phenolic compounds and lipophilic constituents such as vitamin E, unsaturated fatty acids, and phytosterols, GSO has recently received much attention as a source of health-functional ingredients (Xue, Pan, Huang et al., 2020a).

Several studies have demonstrated that GSO has antimicrobial, antioxidant, anti-inflammatory, antimutagenic, and anticancer properties (Harbeoui et al., 2019, Martin et al., 2020). Some of GSO’s phenolic compounds, which act in cell cycle modulation and are cytotoxic to tumor cells while not compromising healthy cells, contribute to its anticancer potential (Huang et al., 2012; Xue, Pan, Huang et al., 2020b). In addition, GSO has been used as the basis of lipid nanocarriers in order to improve the therapeutic efficacy of antitumor drugs (Lacatusu et al., 2015). Furthermore, GSO can be a good candidate of leukemia complementary therapy as it prevents cytotoxicity on healthy cells and reduces the severity of chemotherapy side effects (Sahin et al., 2012). Given the potential clinical utility of CP and the promising benefits of GSO, we hypothesized that combining GSO and CP would enhance CP's anti-cancer effect in TSCC and induce cell cycle arrest, apoptosis, and inhibit angiogenesis. Thus, this study was conducted to investigate the efficacy of combining CP and GSO in the treatment of tongue carcinoma using a human tongue carcinoma cell line. We hope that our findings would change the therapeutic directions in patients with TSCC by introducing new natural products like GSO as adjuvant therapy to enhance the anti-cancer effects of chemotherapeutic agents.