Drug Candidates for the Treatment of Oral Cancer and Oral Cancer Pain

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 25 June 2024 | Viewed by 9432

Special Issue Editor


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Guest Editor
Department of Comprehensive Dentistry, The University of Texas Health Center, San Antonio, TX 78229-3900, USA
Interests: oral cancer; oral cancer pain; drug discovery; natural compounds; small molecule inhibitors

Special Issue Information

Dear Colleagues,

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and its incidence is ever-increasing. The majority (60%) of tumors are located in the oral cavity (oral squamous cell carcinoma; OSCC) and are notoriously diagnosed in advanced stages (stage 3 and 4), resulting in high morbidity and high mortality rates. However, when they are discovered in early stages (stage 1 and 2), there is an 80% five-year survival rate. This is due to improvements in surgical techniques for early disease. In spite of advances in existing therapies and development of new treatment strategies (e.g., targeted therapies and small molecule inhibitors), very few efficacious drugs have been developed over the past 50 years to treat advanced and recurrent oral cancers. Recently, immunotherapies have shown great promise when used in conjunction with other standard therapies (chemo- and radiotherapies); however, the response rates remain relatively low, leaving a very large patient population in need of new therapeutic options. In addition, OSCC is the most painful cancer type there is. These patients rapidly develop tolerance to opioids, the mainstay therapy for oral cancer pain. Hence, many patients are left with no efficacious analgesics while battling this insidious disease. The journal Pharmaceuticals invites both reviews and original articles detailing novel therapeutic targets, drug candidates, and treatment strategies for oral cancer and oral cancer pain. Topics include natural compounds, small molecule inhibitors, immunotherapies, novel targets/biomarkers, drug repurposing, radiotherapy, and targeted therapies. The collection of manuscripts will be published as a Special Issue of the journal.

Dr. Cara B. Gonzales
Guest Editor

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Keywords

  • oral cancer
  • oral cancer pain
  • drug discovery
  • natural compounds
  • immunotherapy
  • small molecule inhibitors
  • biomarkers

Published Papers (5 papers)

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Research

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21 pages, 8174 KiB  
Article
Michelia compressa-Derived Santamarine Inhibits Oral Cancer Cell Proliferation via Oxidative Stress-Mediated Apoptosis and DNA Damage
by Hsin-I Lu, Kuan-Liang Chen, Ching-Yu Yen, Chung-Yi Chen, Tsu-Ming Chien, Chih-Wen Shu, Yu-Hsuan Chen, Jiiang-Huei Jeng, Bing-Hung Chen and Hsueh-Wei Chang
Pharmaceuticals 2024, 17(2), 230; https://doi.org/10.3390/ph17020230 - 09 Feb 2024
Viewed by 847
Abstract
The anti-oral cancer effects of santamarine (SAMA), a Michelia compressa var. compressa-derived natural product, remain unclear. This study investigates the anticancer effects and acting mechanism of SAMA against oral cancer (OC-2 and HSC-3) in parallel with normal (Smulow–Glickman; S-G) cells. SAMA selectively inhibits [...] Read more.
The anti-oral cancer effects of santamarine (SAMA), a Michelia compressa var. compressa-derived natural product, remain unclear. This study investigates the anticancer effects and acting mechanism of SAMA against oral cancer (OC-2 and HSC-3) in parallel with normal (Smulow–Glickman; S-G) cells. SAMA selectively inhibits oral cancer cell viability more than normal cells, reverted by the oxidative stress remover N-acetylcysteine (NAC). The evidence of oxidative stress generation, such as the induction of reactive oxygen species (ROS) and mitochondrial superoxide and the depletion of mitochondrial membrane potential and glutathione, further supports this ROS-dependent selective antiproliferation. SAMA arrests oral cancer cells at the G2/M phase. SAMA triggers apoptosis (annexin V) in oral cancer cells and activates caspases 3, 8, and 9. SAMA enhances two types of DNA damage in oral cancer cells, such as γH2AX and 8-hydroxy-2-deoxyguanosine. Moreover, all of these anticancer mechanisms of SAMA are more highly expressed in oral cancer cells than in normal cells in concentration and time course experiments. These above changes are attenuated by NAC, suggesting that SAMA exerts mechanisms of selective antiproliferation that depend on oxidative stress while maintaining minimal cytotoxicity to normal cells. Full article
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14 pages, 2483 KiB  
Article
Oral Cancer Pain Includes Thermal Allodynia That May Be Attenuated by Chronic Alcohol Consumption
by Cara B. Gonzales, Jorge J. De La Chapa, Amol M. Patwardhan and Kenneth M. Hargreaves
Pharmaceuticals 2023, 16(4), 518; https://doi.org/10.3390/ph16040518 - 31 Mar 2023
Viewed by 1429
Abstract
Background: Oral cancer is one of the most painful cancer types, and is often refractory to existing analgesics. Oral cancer patients frequently develop a tolerance to opioids, the mainstay of current cancer pain therapy, leaving them with limited therapeutic options. Thus, there is [...] Read more.
Background: Oral cancer is one of the most painful cancer types, and is often refractory to existing analgesics. Oral cancer patients frequently develop a tolerance to opioids, the mainstay of current cancer pain therapy, leaving them with limited therapeutic options. Thus, there is a great need to identify molecular mechanisms driving oral cancer pain in an effort to develop new analgesics. Previous reports demonstrate that oral cancer patients experience intense mechanical pain and pain in function. To date, no studies have examined thermal pain in oral cancer patients or the role that alcohol consumption plays in oral cancer pain. This study aims to evaluate patient-reported pain levels and thermal allodynia, potential molecular mechanisms mediating thermal allodynia, and the effects of alcohol consumption on patient-perceived pain. Methods: This study evaluated human oral squamous cell carcinoma (OSCC) cell lines for their ability to activate thermosensitive channels in vitro and validated these findings in a rat model of orofacial pain. Patient-reported pain in a south Texas OSCC cohort (n = 27) was examined using a visual analog scale (VAS). Covariant analysis examined variables such as tobacco and alcohol consumption, ethnicity, gender, and cancer stage. Results: We determined that OSCC secretes factors that stimulate both the Transient Receptor Potential Ankyrin type 1 channel (TRPA1; noxious cold sensor) and the Transient Receptor Potential Vanilloid type 1 channel (TRPV1; noxious heat sensor) in vitro and that OSCC-secreted factors sensitize TRPV1 nociceptors in vivo. These findings were validated in this cohort, in which allodynia to cold and heat were reported. Notably, subjects that reported regular alcohol consumption also reported lower pain scores for every type of pain tested, with significantly reduced cold-induced pain, aching pain, and burning pain. Conclusion: Oral cancer patients experience multiple types of cancer pain, including thermal allodynia. Alcohol consumption correlates with reduced OSCC pain and reduced thermal allodynia, which may be mediated by TRPA1 and TRPV1. Hence, reduced pain in these patients may contribute to a delay in seeking care, and thus a delay in early detection and treatment. Full article
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16 pages, 1891 KiB  
Article
Assessing Gene Expression Related to Cisplatin Resistance in Human Oral Squamous Cell Carcinoma Cell Lines
by Hyeong Sim Choi, Young-Kyun Kim and Pil-Young Yun
Pharmaceuticals 2022, 15(6), 704; https://doi.org/10.3390/ph15060704 - 03 Jun 2022
Cited by 1 | Viewed by 1888
Abstract
Cisplatin-based chemotherapy has been effectively used to treat oral cancer, but treatment often fails owing to the development of drug resistance. However, the important gene expression alterations associated with these resistances remain unclear. In this study, we aimed to identify the gene expressions [...] Read more.
Cisplatin-based chemotherapy has been effectively used to treat oral cancer, but treatment often fails owing to the development of drug resistance. However, the important gene expression alterations associated with these resistances remain unclear. In this study, we aimed to identify the gene expressions related to cisplatin resistance in oral squamous cell carcinoma (OSCC) cell lines. RNA samples were obtained from three cisplatin-resistant (YD-8/CIS, YD-9/CIS, and YD-38/CIS) and -sensitive (YD-8, YD-9, and YD-38) cell lines. Global gene expression was analyzed using RNA sequencing (RNA-Seq). Differentially expressed genes were determined. Based on the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, functional enrichment and signaling pathways analyses were performed. Candidate genes selected from RNA-Seq analysis were validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The YD-8/CIS and YD-9/CIS samples had very similar expression patterns. qRT-PCR analysis was performed on selected genes commonly expressed between the two samples. The expression levels of 11 genes were changed in cisplatin-resistant samples compared with their parental samples; several of these genes were related to cell adhesion molecules and proteoglycans in cancer pathways. Our data provide candidate genes associated with cisplatin resistance in OSCC, but further study is required to determine which genes have an important role. Nevertheless, these results may provide new ideas to improve the clinical therapeutic outcomes of OSCC. Full article
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Review

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19 pages, 1162 KiB  
Review
Repurposing EGFR Inhibitors for Oral Cancer Pain and Opioid Tolerance
by Maria Daniela Santi, Morgan Zhang, Naijiang Liu, Chi T. Viet, Tongxin Xie, Dane D. Jensen, Moran Amit, Huilin Pan and Yi Ye
Pharmaceuticals 2023, 16(11), 1558; https://doi.org/10.3390/ph16111558 - 03 Nov 2023
Viewed by 1130
Abstract
Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for [...] Read more.
Oral cancer pain remains a significant public health concern. Despite the development of improved treatments, pain continues to be a debilitating clinical feature of the disease, leading to reduced oral mobility and diminished quality of life. Opioids are the gold standard treatment for moderate-to-severe oral cancer pain; however, chronic opioid administration leads to hyperalgesia, tolerance, and dependence. The aim of this review is to present accumulating evidence that epidermal growth factor receptor (EGFR) signaling, often dysregulated in cancer, is also an emerging signaling pathway critically involved in pain and opioid tolerance. We presented preclinical and clinical data to demonstrate how repurposing EGFR inhibitors typically used for cancer treatment could be an effective pharmacological strategy to treat oral cancer pain and to prevent or delay the development of opioid tolerance. We also propose that EGFR interaction with the µ-opioid receptor and glutamate N-methyl-D-aspartate receptor could be two novel downstream mechanisms contributing to pain and morphine tolerance. Most data presented here support that repurposing EGFR inhibitors as non-opioid analgesics in oral cancer pain is promising and warrants further research. Full article
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53 pages, 1492 KiB  
Review
Pharmacological Properties of Trichostatin A, Focusing on the Anticancer Potential: A Comprehensive Review
by Abdelhakim Bouyahya, Nasreddine El Omari, Mohamed Bakha, Tarik Aanniz, Naoual El Menyiy, Naoufal El Hachlafi, Aicha El Baaboua, Mohamed El-Shazly, Mohammed Merae Alshahrani, Ahmed Abdullah Al Awadh, Learn-Han Lee, Taoufiq Benali and Mohammad S. Mubarak
Pharmaceuticals 2022, 15(10), 1235; https://doi.org/10.3390/ph15101235 - 08 Oct 2022
Cited by 11 | Viewed by 3076
Abstract
Trichostatin A (TSA), a natural derivative of dienohydroxamic acid derived from a fungal metabolite, exhibits various biological activities. It exerts antidiabetic activity and reverses high glucose levels caused by the downregulation of brain-derived neurotrophic factor (BDNF) expression in Schwann cells, anti-inflammatory activity by [...] Read more.
Trichostatin A (TSA), a natural derivative of dienohydroxamic acid derived from a fungal metabolite, exhibits various biological activities. It exerts antidiabetic activity and reverses high glucose levels caused by the downregulation of brain-derived neurotrophic factor (BDNF) expression in Schwann cells, anti-inflammatory activity by suppressing the expression of various cytokines, and significant antioxidant activity by suppressing oxidative stress through multiple mechanisms. Most importantly, TSA exhibits potent inhibitory activity against different types of cancer through different pathways. The anticancer activity of TSA appeared in many in vitro and in vivo investigations that involved various cell lines and animal models. Indeed, TSA exhibits anticancer properties alone or in combination with other drugs used in chemotherapy. It induces sensitivity of some human cancers toward chemotherapeutical drugs. TSA also exhibits its action on epigenetic modulators involved in cell transformation, and therefore it is considered an epidrug candidate for cancer therapy. Accordingly, this work presents a comprehensive review of the most recent developments in utilizing this natural compound for the prevention, management, and treatment of various diseases, including cancer, along with the multiple mechanisms of action. In addition, this review summarizes the most recent and relevant literature that deals with the use of TSA as a therapeutic agent against various diseases, emphasizing its anticancer potential and the anticancer molecular mechanisms. Moreover, TSA has not been involved in toxicological effects on normal cells. Furthermore, this work highlights the potential utilization of TSA as a complementary or alternative medicine for preventing and treating cancer, alone or in combination with other anticancer drugs. Full article
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