Mechanisms Involved in Therapeutic Effects of Scutellaria baicalensis Georgi in Oral Squamous Cell Carcinoma Based on Systems Biology and Structural Bioinformatics Approaches.

Objective: Oral squamous cell carcinoma (OSCC) is the most frequent oral cancer, constituting more than 90% of all oral carcinomas. The 5-year survival rate of OSCC patients is not satisfactory, and therefore, there is an urgent need for new practical therapeutic approaches besides the current therapies to overcome OSCC. Scutellaria baicalensis Georgi (SBG) is a plant of the family Lamiaceae with several pharmaceutical properties such as antioxidant, anti-inflammatory, and anticancer effects. Previous studies have demonstrated the curative effects of SBG in OSCC. Methods: A systems biology approach was conducted to identify differentially expressed miRNAs (DEMs) in OSCC patients with a dismal prognosis compared to OSCC patients with a favorable prognosis. A protein interaction map (PIM) was built based on DEMs targets, and the hub genes within the PIM were indicated. Subsequently, the prognostic role of the hubs was studied using Kaplan-Meier curves. Next, the binding affinity of SBG's main components, including baicalein, wogonin, oroxylin-A, salvigenin, and norwogonin, to the prognostic markers in OSCC was evaluated using molecular docking analysis. Results: Survival analysis showed that overexpression of CAV1, SERPINE1, ACTB, SMAD3, HMGA2, MYC, EIF2S1, HSPA4, HSPA5, and IL6 was significantly related to a poor prognosis in OSCC. Besides, molecular docking analysis demonstrated the ΔGbinding and inhibition constant values between SBG's main components and SERPINE1, ACTB, HMGA2, EIF2S1, HSPA4, and HSPA5 were as <-8.00 kcal/mol and nanomolar concentration, respectively. The most salient binding affinity was observed between wogonin and SERPINE1 with a criterion of ΔGbinding < -10.02 kcal/mol. Conclusion: The present results unraveled potential mechanisms involved in therapeutic effects of SBG in OSCC based on systems biology and structural bioinformatics analyses.

Can a cup a day keep cancer away? A systematic review exploring the potential of coffee constituents in preventing oral squamous cell carcinoma.

BACKGROUND: Coffee is one of the most consumed beverages in the world. Containing an abundance of bioactive molecules including polyphenols and flavonoids, the constituents of this beverage may exert antiproliferative, antioxidant and anti-inflammatory effects. METHODS: We conducted a systematic review to summarise the available evidence on the anticancer effects of coffee constituents and their potential therapeutic use for oral squamous cell carcinoma (OSCC). Studies were identified through a comprehensive search of OVID MEDLINE, OVID EMBASE and Web of Science, including articles from any year up to 15 May 2023. RESULTS: Of the 60 reviewed papers, 45 were in vitro, 1 was in silico and 8 were in vivo exclusively. The remaining studies combined elements of more than one study type. A total of 55 studies demonstrated anti-proliferative effects, whilst 12 studies also investigated migration and invasion of neoplastic cells. The constituents studied most frequently were quercetin and epigallocatechin gallate (EGCG), demonstrating various cytotoxic effects whilst also influencing apoptotic mechanisms in cancer cell lines. Dose-dependent responses were consistently found amongst the studied constituents. CONCLUSION: Whilst there was heterogeneity of study models and methods, consistent use of specific models such as SCC25 for in vitro studies and golden hamsters for in vivo studies enabled relative comparability. The constituents of coffee have gained significant interest over the last 30 years, particularly in the last decade, and present an area of interest with significant public health implications. Currently, there is a paucity of literature on utilization of active coffee constituents for the therapeutic treatment of oral cancers.

Antitumor effect of toosendanin on oral squamous cell carcinoma via suppression of p-STAT3.

BACKGROUND: Toosendanin (TSN) exhibits potent antitumor activity against various tumor cell lines. However, its efficacy against oral squamous cell carcinoma (OSCC) remains unknown. Here, we investigated the effects of TSN on OSCC cells in vitro and verified them in vivo using a patient-derived xenograft (PDX) model. METHODS: The effect of TSN on OSCC cells was investigated by cytotoxicity assays and flow cytometry. The expression of proteins was detected by western blotting. An OSCC PDX model was constructed to further investigate the role of TSN in regulating the function of OSCC. RESULTS: The cell viability of CAL27 and HN6 cells decreased as the concentration of TSN increased within the experimental range. Compared with controls, TSN at lower doses inhibited cell proliferation and induced apoptosis through S-phase cell cycle arrest. TSN inhibited OSCC cell proliferation by downregulating the STAT3 pathway through the inhibition of STAT3 phosphorylation. After successful construction of the OSCC PDX model with high pathological homology to the primary tumor and treatment with an intraperitoneal injection of TSN, we showed that TSN significantly reduced the tumor size of the PDX model mice without obvious toxicity. CONCLUSIONS: Both in vitro and in vivo, TSN significantly inhibits the proliferation and promoted apoptosis of OSCC cells. Furthermore, TSN demonstrates potent inhibition of STAT3 phosphorylation, indicating its potential as a promising therapeutic agent for OSCC. Therefore, TSN holds great promise as a viable drug candidate for the treatment of OSCC.

Therapeutic Effects of Perilla Phenols in Oral Squamous Cell Carcinoma.

The herbal medicine perilla leaf extract (PLE) exhibits various pharmacological properties. We showed that PLE inhibits the viability of oral squamous cell carcinoma (OSCC) cells. HPLC analysis revealed that caffeic acid (CA) and rosmarinic acid (RA) are the two main phenols in PLE, and reduced OSCC cell viability in a dose-dependent manner. The optimal CA/RA combination ratio was 1:2 at concentrations of 300-500 µM but had no synergistic inhibitory effect on the viability of OSCC cells. CA, RA, or their combination effectively suppressed interleukin (IL)-1ß secretion by OSCC OC3 cells. Long-term treatment with CA and CA/RA mixtures, respectively, induced EGFR activation, which might cause OC3 cells to become EGFR-dependent and consequently increased the sensitivity of OC3 cells to a low dose (5 µM) of the EGFR tyrosine kinase inhibitor gefitinib. Chronic treatment with CA, RA, or their combination exhibited an inhibitory effect more potent than that of low-dose (1 µM) cisplatin on the colony formation ability of OSCC cells; this may be attributed to the induction of apoptosis by these treatments. These findings suggest that perilla phenols, particularly CA and RA, can be used as adjuvant therapies to improve the efficacy of chemotherapy and EGFR-targeted therapy in OSCC.

Sentinel node-assisted neck dissection in advanced oral squamous cell carcinoma-A new protocol for staging and treatment.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is used to improve the staging of and guide treatment in patients with early-stage T1-T2 N0 oral squamous cell carcinoma (OSCC). The role of sentinel nodes (SNs) and the use of SN-technique in advanced OSCC (T3-T4 and/or N+) remain to be evaluated. This study investigates the nodal drainage and the rate of positive SNs (SNs+) in all stages of OSCC. MATERIALS AND METHODS: In total, 85 patients with T1-T4 OSCC diagnosed 2019-2021 were included. We used a prolonged interval between peritumoral injection of radionuclide and SPECT-CT to include all SNs. RESULTS: Patients with advanced OSCC presented a higher proportion of contralateral lymphatic drainage and a higher rate of SN+ compared to patients with early-stage disease. T3-T4 and N+ tumors presented a tendency for a higher rate of contralateral lymphatic drainage compared to T1-T2 and N0 tumors (p = 0.1). The prevalence of positive nodes (SNs+) was higher among patients with advanced disease, T3-T4 versus T1-T2 (p = 0.0398). CONCLUSION: SN-assisted ND enables identification and removal of all SNs + and has the potential for more accurate staging and could possibly give prognostic advantages regarding regional recurrence for all OSCC patients, especially among those with advanced disease. The precise localization of the SNs + also suggests that a more individualized ND approach might be possible in the future even for patients with advanced OSCC.

Role and regulation of GLUT1/3 during oral cancer progression and therapy resistance.

OBJECTIVE: This study aimed to determine whether glucose transporter-1/3 (GLUT1/3) increased expression could contribute to oral tumor severity. Furthermore, this study detected whether GLUT1/3 mRNA/protein was associated with oncogenic transcription factors (HIF1α, AP1 and NFκB) and whether by blocking GLUT1 along with cisplatin could sensitize drug-resistant OSCC cells. DESIGN: We used 120 post-operated human tissue samples, including 35 primary tumors (PT), 43 invasive tumors (N1-3), 17 recurrent chemoradiation-resistant tumors (RCRT), and 25 PT-adjacent normal tissues (AN). The cisplatin-resistant (CisR-SCC4/9) cells were generated using a drug escalation strategy from parental SCC4/9 cells. The BAY-876 treatment blocked GLUT1 in OSCC cells. Western Blot, Immunohistochemistry, and reverse transcription polymerase chain reaction (RT-PCR) were used to detect various proteins and mRNA. Cell survival was determined by MTT assay. RESULTS: GLUT1/3 expression was observed more in PT over AN tissue (PT > AN), N1-3 > PT, and .RCRT > PT. GLUT1 expression was maximum in the RCRT group and CisR-SCC4/9 cells over their parental counterpart, linked with tumor size (p=0.0037) and loco-regional invasiveness (p=0.0422). GLUT1/3 mRNA/protein was correlated (positively) with oncogenic transcription factors (TFs) like HIF1α, AP1 and NFκB. We found the degree of positive correlation of these TFs with GLUT1/3 was in the order c-Jun > HIF1α > Fra-2 > NFκB > c-Fos. Treatment of BAY-876 and cisplatin-induced cell death in both CisR-SCC4/9 cells, possibly by triggering apoptosis and autophagy. CONCLUSION: Collectively, our results demonstrated increased GLUT1/3 overexpression linked with oral tumor severity like invasion and therapy resistance, and it was powered mainly by c-Jun (AP1). Blocking GLUT1 receptors and cisplatin application can sensitize CisR-OSCC cells.

Extract of Ficus septica modulates apoptosis and migration in human oral squamous cell carcinoma cells.

According to the alarming statistical analysis of global cancer, there are over 19 million new diagnoses and more than 10 million deaths each year. One such cancer is the oral squamous cell carcinoma (OSCC), which requires new therapeutic strategies. Ficus septica extract has been used in traditional medicine to treat infectious diseases. In this study, we examined the anti-proliferative effects of an extract of F. septica bark (FSB) in OSCC cells. Our results showed that FSB caused a concentration-dependent reduction in the viability of SCC2095 OSCC cells, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and was less sensitive to fibroblasts. In addition, FSB induced apoptosis by activating caspases, accompanied by the modulation of Akt/mTOR/NF-κB and mitogen-activated protein kinase signaling. Moreover, FSB increased reactive oxygen species generation in a concentration-dependent manner in SCC2095 cells. Furthermore, FSB inhibited cell migration and modulated the levels of the cell adhesion molecules including E-cadherin, N-cadherin, and Snail in SCC2095 cells. Pinoresinol, a lignan isolated from FSB, showed antitumor effects in SCC2095 cells, implying that this compound might play an important role in FSB-induced OSCC cell death. Taken together, FSB is a potential anti-tumor agent against OSCC cells.

[Influencing factors of nutritional status and change in 50 patients with oral squamous cell carcinoma during treatment].

PURPOSE: To investigate the changes of nutritional status in patients with oral squamous cell carcinoma(OSCC) and analyze the influencing factors during treatment. METHODS: Anthropometry (weight, BMI, waistline, middle circumference of left and right upper arms) and laboratory index(serum prealbumin, serum albumin, transferrins, 25-hydroxyvitamin D) were measured to represent the nutritional status of 50 patients with OSCC before operation, two days, one month and three months after operation. SPSS 24.0 software package was used for statistical analysis of the data, and influencing factors of nutrition risk in OSCC patient were analyzed with binary logistic regression model. RESULTS: Univariate and multivariate analysis showed that advanced age(OR=1.127,95%CI: 1.053-1.207), low educational level (OR=5.250, 95%CI: 1.147-21.796), smoking(OR=6.182, 95%CI: 1.631-23.433), alcohol use(OR=5.227, 95%CI: 1.336-20.450), chemoradiotherapy (OR=3.984, 95%CI: 1.199-13.242), free flap surgery (OR=8.000, 95%CI: 2.060-31.068), tracheostomy(OR=3.960, 95%CI: 1.069-14.671), cervical lymph node metastasis(OR=4.821, 95%CI: 1.418-16.399), buccal carcinoma(OR=9.000, 95%CI:1.140-71.038), tongue cancer(OR=7.200, 95%CI: 1.081-47.962), tumor stage T3-4(OR=3.542, 95%CI: 1.066-11.771) were independent influencing factors of the nutritional status of patients with OSCC. CONCLUSIONS: Aging, low educational level, smoking history and drinking history in the general demographic characteristics of patients, and chemoradiotherapy, free flap surgery, tracheostomy during treatment, as well as buccal carcinoma, tongue cancer, advanced stage and cervical lymph node metastasis are clinical characteristics, which affect the nutrition level during the treatment for OSCC patients.

Deoxypodophyllotoxin Induces ROS-Mediated Apoptosis by Modulating the PI3K/AKT and p38 MAPK-Dependent Signaling in Oral Squamous Cell Carcinoma.

Deoxypodophyllotoxin (DPT), a naturally occurring flavonolignan, possesses several pharmacological properties, including anticancer property. However, the mechanisms underlying DPT mode of action in oral squamous cell carcinoma (OSCC) remain unknown. This study aimed to investigate the anticancer effects of DPT on OSCC and the underlying mechanisms. Results of the MTT assay revealed that DPT significantly reduced the cell viability in a time- and dose-dependent manner. Flow cytometry analysis revealed that DPT induces apoptosis in OSCC cells in a dose-dependent manner. Moreover, DPT enhanced the production of mitochondrial reactive oxygen species (ROS) in OSCC cells. Mechanistically, DPT induced apoptosis in OSCC cells by suppressing the PI3K/AKT signaling pathway while activating the p38 MAPK signaling to regulate the expression of apoptotic proteins. Treatment with SC79, an AKT activator, reversed the effects of DPT on AKT signaling in OSCC cells. Taken together, these results provide the basis for the use of DPT in combination with conventional chemotherapy for the treatment of oral cancer.

Effect of low-level light therapy before radiotherapy in oral squamous cell carcinoma: An in vitro study.

Radiation therapy for head and neck squamous cell carcinoma (HNSCC) is associated with several complications. Although photobiomodulation (PBM) has radioprotective effects in normal tissue, it could also enhance the growth of neoplastic cells. Thus, the present study aimed to investigate the cellular response of oral squamous cell carcinoma with pre-exposure to low-level phototherapy before radiotherapy. SCC9, Cal-27, A431, and HaCaT cell lines were subjected to low-level light therapy and radiotherapy. The cells were treated with a single energy density (300 J/cm2) of a light-emitting diode (660 nm) prior to ionizing radiation at different doses (0, 2, 4, and 6 Gy). After 24 h, wound scratch, proliferation, clonogenic cell survival, cell death, and reactive oxygen species (ROS) analyses were performed to evaluate cell response. The cell lines pre-exposed to PBM at the analyzed dosage were radiosensitive. The treatment significantly reduced cell proliferation and clonogenic cell survival. Migration and cell death assays also revealed positive results, with the treatment group showing lower rate of migration and higher cell death than did the control group. Moreover, PBM effectively increased the intracellular levels of ROS. PBM at 300 J/cm2 is a promising radiosensitizing modality to reduce the radiation dose and avoid the intolerable side effects of radiotherapy for HNSCC, thus increasing the probability of successful treatment. However, further studies are needed to support and confirm the results.

An unusual intraoral lipoma: case report and review of the literature.

Lipoma is a common tumor of soft tissue with rare occurrence in oral cavity accounting for only 1-4% of benign oral tumours. It may be noticed only during routine dental examinations. Most of them rarely cause pain, resulting in delay to seek treatment. Lipoma of the oral cavity may occur in any region. The buccal mucosa, tongue, and floor of the mouth are among the common locations. A case of large intraoral lipoma occurring in mental region in a 60-year-old female patient is reported. It was treated surgically under local anesthesia, and 6 month follow up showed excellent healing without any recurrence.

Survival and clinicopathological characteristics of cT4b oral squamous cell carcinoma based on different treatment modalities: A single-center retrospective study.

INTRODUCTION: Primary surgical treatment for oral squamous cell carcinoma (OSCC) is reserved for T1 to T4a tumors, but not for T4b tumors, according to the present National Comprehensive Cancer Network clinical practice guidelines. In this retrospective study, we aimed to determine the association between the clinicopathological characteristics and different treatment modalities for T4b OSCC based on whether patients received primary surgical treatment. Therefore, we conducted a survival analysis based on different treatment modalities. METHODS: This retrospective cohort study enrolled 125 patients with clinical stage T4b OSCC who received treatment and were followed up at Changhua Christian Hospital between January 1, 2008 and December 31, 2018. RESULTS: Overall, 81 patients received primary surgical treatment and 44 received primary nonsurgical treatment. Comparison of the clinicopathological characteristics between those who did and did not undergo surgery revealed no significant differences in age at tumor diagnosis, tumor location, clinical N stage, and involved tumor area based on computed tomography or magnetic resonance imaging, or stratified Charlson Comorbidity Index scores. In the survival analysis, Kaplan-Meier curves revealed that patients who received treatment modalities including surgery exhibited better survival than those who received treatment modalities that did not include surgery. CONCLUSIONS: In the present study, patients with T4b OSCC treated with primary surgery had a better overall survival rate than those who received nonsurgical treatment. In the future, it will be necessary for clinicians worldwide to report the treatment outcomes of patients with T4b OSCC based on the common criteria.

Hypovitaminosis D, oral potentially malignant disorders, and oral squamous cell carcinoma: a systematic review.

BACKGROUND: Oral squamous cell carcinoma (OSCC) and potentially malignant oral disorders (OPMDs) could be associated with low levels of vitamin D. This systematic review aimed to determine the relationship between serum levels of vitamin D with OPMDs and OSCC. MATERIAL AND METHODS: This review was conducted according to Cochrane guidelines (PROSPERO CRD42020207382) on literature retrieved from the PubMed, Cochrane, and Web of Science databases. The antecedents extracted were study design, methodology, sample (country, number of patients, age, and sex), oral manifestations (type of lesion, location, prevalence, and follow-up), serum vitamin D levels or use of vitamin D supplements, results, and conclusions. RESULTS: Twelve articles were selected. Some of the most relevant findings were alterations in vitamin D could favor the progress of OPMDs to OSCC. Higher levels of vitamin D can increase levels of anti-inflammatory mediators, CD4+ T lymphocytes and CD8+ T lymphocytes and CD3+ T lymphocytes in intratumoral tissue. The normalization of vitamin D levels in patients with OSCC can increased cytotoxic activity of natural killer cells, favoring antitumor immune response. Vitamin D supplemented can lower adverse effects associated with chemotherapy like mucositis and pain. Tobacco can increase risk of developing OSCC altering vitamin D levels. CONCLUSIONS: Hypovitaminosis D could increase risk of developing OSCC from OPMDs, thus altering the immune response and it is associated with a lower survival rate in patients with OSCC, a greater recurrence of tumors in patients who underwent surgical treatment, and an increase in adverse reactions to chemotherapy. The use of vitamin D supplements can be a complement to primary therapy to prevent the recurrence of lesions and reduce adverse events associated with treatment.

Glaucocalyxin A impairs tumor growth via amplification of the ATF4/CHOP/CHAC1 cascade in human oral squamous cell carcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: The natural extract glaucocalyxin A (GLA), purified from the aboveground sections of the Chinese traditional medicinal herb Rabdosia japonica (Burm. f.) Hara var. glaucocalyx (Maxim.) Hara, has various pharmacological benefits, such as anti-bacterial, anti-coagulative, anti-neoplastic, and anti-inflammatory activities. Although GLA has shown anti-tumor activity against various cancers, the therapeutic potential and biological mechanisms of GLA remain to be further explored in oral squamous cell carcinoma (OSCC). AIM OF THE STUDY: This study aimed to elucidate the therapeutic potential and regulatory mechanisms of GLA in OSCC. MATERIALS AND METHODS: The cell proliferation and apoptosis effects of GLA were analyzed by CCK-8, clone formation, Annexin V/PI staining, and apoptotic protein expression in vitro. An OSCC xenograft model was applied to confirm the anti-neoplastic effect in vivo. Furthermore, the changes of reactive oxygen species (ROS) were determined by DCFH-DA probe and GSH/GSSG assay, and inhibited by the pan-caspase inhibitor Z-VAD(OMe)-FMK and the ROS scavenger N-acetylcysteine (NAC). The modulation of GLA on mitochondria and ER-dependent apoptosis pathways was analyzed by JC-1 probe, quantitative real-time PCR, and Western blot. Finally, public databases, clinical samples, and transfection cells were analyzed to explore the importance of GLA's indirect targeting molecule CHAC1 in OSCC. RESULTS: GLA significantly inhibited cell proliferation and induced apoptosis in vitro and in vivo. GLA perturbed the redox homeostasis, and cell apoptosis was totally rescued by Z-VAD(OMe)-FMK and NAC. Furthermore, GLA activated the mitochondrial apoptosis pathway. Simultaneously, the overexpression and knockdown of CHAC1 dramatically affected GLA-mediated apoptosis. The endoplasmic reticulum stress-associated ATF4/CHOP signal was identified to participate in GLA-upregulated CHAC1 expression. Finally, we found that CHAC1 expression was lower in OSCC compared with normal tissues and positively correlated with 4-Hydroxynonenal (4-HNE) level. High CHAC1 expression also indicated better overall survival. Moreover, CHAC1 selectively regulated the viability of oral cancer cells. CONCLUSION: GLA is a promising therapeutic agent that activates the ROS-mediated ATF4/CHOP/CHAC1 axis in OSCC patients.

Molecular Mechanisms of Malignant Transformation of Oral Submucous Fibrosis by Different Betel Quid Constituents-Does Fibroblast Senescence Play a Role?

Betel quid (BQ) is a package of mixed constituents that is chewed by more than 600 million people worldwide, particularly in Asia. The formulation of BQ depends on a variety of factors but typically includes areca nut, betel leaf, and slaked lime and may or may not contain tobacco. BQ chewing is strongly associated with the development of potentially malignant and malignant diseases of the mouth such as oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC), respectively. We have shown recently that the constituents of BQ vary geographically and that the capacity to induce disease reflects the distinct chemical composition of the BQ. In this review, we examined the diverse chemical constituents of BQ and their putative role in oral carcinogenesis. Four major areca alkaloids-arecoline, arecaidine, guvacoline and guvacine-together with the polyphenols, were identified as being potentially involved in oral carcinogenesis. Further, we propose that fibroblast senescence, which is induced by certain BQ components, may be a key driver of tumour progression in OSMF and OSCC. Our study emphasizes that the characterization of the detrimental or protective effects of specific BQ ingredients may facilitate the development of targeted BQ formulations to prevent and/or treat potentially malignant oral disorders and oral cancer in BQ users.

Prospective Phase II Open-Label Randomized Controlled Trial to Compare Mandibular Preservation in Upfront Surgery With Neoadjuvant Chemotherapy Followed by Surgery in Operable Oral Cavity Cancer.

PURPOSE: The objective of this study was to explore the potential role and safety of neoadjuvant chemotherapy (NACT) in tumor shrinkage and resultant mandibular preservation in oral cancers compared with conventional surgical treatment. METHODS: This study was a single-center, randomized, phase II trial of treatment-naive histologically confirmed squamous cell carcinoma of the oral cavity with cT2-T4 and N0/N+, M0 (American Joint Committee on Cancer, seventh edition) stage, necessitating resection of the mandible for paramandibular disease in the absence of clinicoradiologic evidence of bone erosion. The patients were randomly assigned (1:1) to either upfront surgery (segmental resection) followed by adjuvant treatment (standard arm [SA]) or two cycles of NACT (docetaxel, cisplatin, and fluorouracil) at 3-week intervals (intervention arm [IA]), followed by surgery dictated by postchemotherapy disease extent. All patients in the IA received adjuvant chemoradiotherapy, and patients in the SA were treated as per final histopathology report. The primary end point was mandible preservation rate. The secondary end points were disease-free survival and treatment-related toxicity. RESULTS: Sixty-eight patients were enrolled over 3 years and randomly assigned to either SA (34 patients) or IA (34 patients). The median follow-up was 3.6 years (interquartile range, 0.95-7.05 years). Mandibular preservation was achieved in 16 of 34 patients (47% [95% CI, 31.49 to 63.24]) in the IA. The disease-free survival (P = .715, hazard ratio 0.911 [95% CI, 0.516 to 1.607]) and overall survival (P = .747, hazard ratio 0.899 [95% CI, 0.510 to 1.587]) were similar in both the arms. Complications were similar in both arms, but chemotherapy-induced toxicity was observed in the majority of patients (grade III: 14, 41.2%; grade IV: 11, 32.4%) in the IA. CONCLUSION: NACT plays a potential role in mandibular preservation in oral cancers with acceptable toxicities and no compromise in survival. However, this needs to be validated in a larger phase III randomized trial.

Poor tumor differentiation is an independent adverse prognostic variable in patients with locally advanced oral cavity cancer--Comparison with pathological risk factors according to the NCCN guidelines.

METHODS: We sought to compare the prognostic impact of tumor differentiation with respect to adverse risk factors (RFs) identified by the National Comprehensive Cancer Network (NCCN) guidelines--including extranodal extension (ENE), positive/close margins, perineural invasion, lymphatic invasion, and vascular invasion--in patients with locally advanced oral cavity squamous cell carcinoma (OCSCC). RESULTS: Between 1996 and 2018, 1179 consecutive patients with first primary pT3-4 OCSCC were included. A three-level grading system was adopted--in which the final classification was assigned according to the most prevalent tumor grade. We identified 382/669/128 patients with well/moderately/poorly differentiated tumors, respectively. Compared with well/moderately differentiated tumors, poorly differentiated OCSCC had a higher prevalence of the following variables: female sex (4%/6%/11%), ENE, (14%/36%/61%), positive margins (0.5%/2%/4%), close margins (10%/14%/22%), perineural invasion (22%/50%/63%), lymphatic invasion (2%/9%/17%), vascular invasion (1%/4%/10%), and adjuvant therapy (64%/80%/87%). The 5-year rates of patients with well/moderately/poorly differentiated OCSCC were as follows: local control (LC, 85%/82%/84%, p = 0.439), neck control (NC, 91%/83%/70%, p < 0.001), distant metastases (DM, 6%/18%/40%, p < 0.001), disease-free survival (DFS, 78%/63%/46%, p < 0.001), disease-specific survival (DSS, 85%/71%/49%, p < 0.001), and overall survival (OS, 68%/55%/39%, p < 0.001). Multivariable analysis identified the following variables as independent prognosticators for 5-year outcomes: ENE (LC/NC/DM/DFS/DSS/OS), poorly differentiated tumors (NC/DM/DFS/DSS/OS), positive margins (LC/DFS), lymphatic invasion (DFS/DSS/OS), perineural invasion (DM), and age ≥65 years (OS). CONCLUSIONS: In addition to ENE, poor tumor differentiation was identified as the second most relevant adverse RF for patients with pT3-4 OCSCC. We suggest that the NCCN guidelines should include poor tumor differentiation as an adverse RF to refine and tailor clinical management.

Combinatorial treatment with Gefitinib and Bay11-7085 sensitizes primary Gefitinib-resistant OSCC cells by influencing the EGFR- NFκB signaling axis.

EGFR-targeted therapies are reported to yield modest effect in OSCC. Activation of NFκB signaling is considered as molecular driver of EGFR inhibitor resistance in various cancers. In this scenario, present study focused on the molecular crosstalk between EGFR and NFκB signaling pathways and its therapeutic importance in OSCC. The EGFR- NFκB p65 co-expressed human OSCC cell lines UPCI:SCC066, UPCI:SCC040 and UM-SCC083B were used for in vitro studies. Recombinant human EGF, siRNAs, Western blot and qRT-PCR were used to dissect the molecular crosstalk between EGFR-NFκB signaling pathways in OSCCs. The effect of NFκB p65 knockdown on cancer hallmarks was studied by respective functional assays and RNA-Seq analysis was performed to identify the differentially expressed genes upon NFκB p65 knockdown. Gefitinib and Bay 11-7085 combination treatment was done to study the chemotherapeutic potential of EGFR- NFκB axis. Significant positive correlation between EGFR and NFκB p65 expression was observed in Head and Neck TCGA data set. EGFR induction or knockdown respectively stimulate or impair the NFκB signaling in EGFR- NFκB p65 co-expressed OSCC cell lines. NFκB p65 knockdown causes apoptosis and suppresses the viability, colony formation, migration, invasion, and spheroid formation. Using RNA-seq analysis, we identified PIK3CD as the NFκB target gene, which is commonly involved in these functions. Gefitinib and Bay 11-7085 combination treatment was found to be useful in chemosensitizing the Gefitinib-resistant OSCC cells by capitulating the EGFR- NFκB signaling axis. Combination treatment using Gefitinib and Bay 11-7085 enhanced the apoptosis and reduced cell viability and colony formation in a synergistic way. Our data demonstrated that EGFR-NFκB signaling axis plays a key role in the pathogenesis of OSCCs. Therefore, simultaneous therapeutic intervention of these pathways may be a good alternative approach for the management of OSCCs.

Actein Antagonizes Oral Squamous Cell Carcinoma Proliferation through Activating FoxO1.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is among the most prevalent head and neck malignancies globally, and it is associated with high mortality rates. Actein is one of the primary active components extractable from the rhizomes of Cimicifuga foetida. This study aimed to evaluate the anti-OSCC effects of actein and evaluate the potential underlying mechanisms. METHODS AND RESULTS: CCK-8 cell proliferation experiments demonstrated significant dose- and time-dependent anti-OSCC effects of actein, while actein had weak cytotoxic effects on normal oral cell lines. Flow cytometry for cell cycle evaluation revealed that actein could induce cell cycle arrest at the G1 phase among OSCC cell lines. In our Annexin V/PI double staining apoptosis analysis, actein induced significant apoptosis among OSCC cells, with upregulation of Bax and downregulation of Bcl-2. Our mechanistic study implicated the involvement of the Akt/FoxO1 pathway in the anti-OSCC effects of actein. Akt1 and Akt2 expression significantly decreased in association with the FoxO1 upregulation. Furthermore, Bim and p21 were significantly upregulated, while survivin expression was downregulated. Finally, actein treatment was associated with significant p-Akt downregulation and p-FoxO1 upregulation in OSCC cells, demonstrating the validated roles of Akt/FoxO1 in actein-mediated OSCC cell apoptosis and cell cycle arrest. FoxO1 knockdown significantly reversed the anti-OSCC effects of actein. Additionally, a xenograft model indicated that actein could inhibit OSCC cell growth in vivo. CONCLUSIONS: Our findings demonstrated that actein could be a strong anti-OSCC candidate. Further evaluations of its safety and effectiveness are necessary before it can be considered for clinical use.