A Mechanistic Review of Methotrexate and Celecoxib as a Potential Metronomic Chemotherapy for Oral Squamous Cell Carcinoma

Kamal, Mehta Vedant; Rao, Mahadev; Damerla, Rama Rao; Pai, Ananth; Sharan, Krishan; Palod, Akhil; Shetty, Priya B.; Usman, Nawaz; Kumar, Naveena A. N.

doi:10.1080/07357907.2022.2139840

Cited by 6 publications

(9 citation statements)

References 67 publications

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“…43 Drugs, such as celecoxib and methotrexate (a combination used in low-dose oral metronomic chemotherapy) and bevacizumab, a monoclonal antibody against VEGF, have demonstrated encouraging results in clinical trials to reduce angiogenesis and improve oncological outcomes in specific malignancies. 44,45 Our findings on the intriguing expression pattern and clinical implications of PTGS2 and VEGF signalling genes provide a foundation for further investigation with comprehensive multi-omics approach to gain deeper insights into the molecular complexity of the disease. However, the study's limitations, including the small sample size, requires validation with a larger patient cohort.…”

Section: Discussionmentioning

confidence: 92%

“…VEGFB and KDR are often associated with angiogenesis‐mediated resistance because they stabilise the tumour microenvironment by ensuring an adequate supply of oxygen and other nutrients required for tumour growth, further adjusting the tumour microenvironment for optimum disease progression 43 . Drugs, such as celecoxib and methotrexate (a combination used in low‐dose oral metronomic chemotherapy) and bevacizumab, a monoclonal antibody against VEGF , have demonstrated encouraging results in clinical trials to reduce angiogenesis and improve oncological outcomes in specific malignancies 44,45 …”

Section: Discussionmentioning

confidence: 99%

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Expression of PTGS2 along with genes regulating VEGF signalling pathway and association with high‐risk factors in locally advanced oral squamous cell carcinoma

Kamal,

Damerla,

Parida

et al. 2024

Cancer Medicine

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BackgroundPTGS2 encodes cyclooxygenase‐2 (COX‐2), which catalyses the committed step in prostaglandin synthesis. Various in vivo and in vitro data suggest that COX‐2 mediates the VEGF signalling pathway. In silico analysis performed in TCGA, PanCancer Atlas for head and neck cancers, demonstrated significant expression and co‐expression of PTGS2 and genes that regulate VEGF signalling. This study was designed to elucidate the expression pattern of PTGS2 and genes regulating VEGF signalling in patients with locally advanced oral squamous cell carcinoma (OSCC).MethodologyTumour and normal tissue samples were collected from patients with locally advanced OSCC. RNA was isolated from tissue samples, followed by cDNA synthesis. The cDNA was used for gene expression analysis (RT‐PCR) using target‐specific primers. The results obtained were compared with the in silico gene expression of the target genes in the TCGA datasets. Co‐expression analysis was performed to establish an association between PTGS2 and VEGF signalling genes.ResultsTumour and normal tissue samples were collected from 24 OSCC patients. Significant upregulation of PTGS2 expression was observed. Furthermore, VEGFA, KDR, CXCR1 and CXCR2 were significantly upregulated in tumour samples compared with paired normal samples, except for VEGFB, whose expression was not statistically significant. A similar expression pattern was observed in silico, except for CXCR2 which was highly expressed in the normal samples. Co‐expression analysis showed a significant positive correlation between PTGS2 and VEGF signalling genes, except for VEGFB which showed a negative correlation.ConclusionPTGS2 and VEGF signalling genes are upregulated in OSCC, which has a profound impact on clinical outcomes.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Expression of PTGS2 along with genes regulating VEGF signalling pathway and association with high‐risk factors in locally advanced oral squamous cell carcinoma

Kamal,

Damerla,

Parida

et al. 2024

Cancer Medicine

Self Cite

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“…Drugs like celecoxib that specifically act on the COX-2 enzyme, inhibiting its function, have been proven clinically to be very efficient in curbing cancer progression, especially in head and neck cancers. 32 COX-2 inhibitors have now been employed in various multi-drug chemotherapeutic regimens to treat head and neck cancers, like metronomic chemotherapy, which acts on various druggable targets, including COX-2, and has been shown to increase patient survival. 32 , 33 …”

Section: Discussionmentioning

confidence: 99%

“… 32 COX-2 inhibitors have now been employed in various multi-drug chemotherapeutic regimens to treat head and neck cancers, like metronomic chemotherapy, which acts on various druggable targets, including COX-2, and has been shown to increase patient survival. 32 , 33 …”

Section: Discussionmentioning

confidence: 99%

Prostaglandin-endoperoxide synthase 2 (PTGS2) gene expression and its association with genes regulating the VEGF signaling pathway in head and neck squamous cell carcinoma

Kamal

Damerla

Dikhit

et al. 2023

Journal of Oral Biology and Craniofacial Research

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“…Metronomic therapy has also been tested in patients with metastatic breast cancer, where it resulted in better outcomes compared to conventional dosing [ 15 ]. In head and neck cancers, studies have shown that low-dose methotrexate and celecoxib modulates immune response, angiogenesis and cytotoxic action [ 16 ], and maintenance oral metronomic chemotherapy improved overall and progression-free survivals with decreased toxicity in patients with metastatic/recurrent nasopharyngeal carcinoma [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization

2023

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Implementation of effective cancer treatment strategies requires consideration of how the spatiotemporal heterogeneities within the tumor microenvironment (TME) influence tumor progression and treatment response. Here, we developed a multi-scale three-dimensional mathematical model of the TME to simulate tumor growth and angiogenesis and then employed the model to evaluate an array of single and combination therapy approaches. Treatments included maximum tolerated dose or metronomic (i.e., frequent low doses) scheduling of anti-cancer drugs combined with anti-angiogenic therapy. The results show that metronomic therapy normalizes the tumor vasculature to improve drug delivery, modulates cancer metabolism, decreases interstitial fluid pressure and decreases cancer cell invasion. Further, we find that combining an anti-cancer drug with anti-angiogenic treatment enhances tumor killing and reduces drug accumulation in normal tissues. We also show that combined anti-angiogenic and anti-cancer drugs can decrease cancer invasiveness and normalize the cancer metabolic microenvironment leading to reduced hypoxia and hypoglycemia. Our model simulations suggest that vessel normalization combined with metronomic cytotoxic therapy has beneficial effects by enhancing tumor killing and limiting normal tissue toxicity.

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A Mechanistic Review of Methotrexate and Celecoxib as a Potential Metronomic Chemotherapy for Oral Squamous Cell Carcinoma

Cited by 6 publications

References 67 publications

Expression of PTGS2 along with genes regulating VEGF signalling pathway and association with high‐risk factors in locally advanced oral squamous cell carcinoma

Expression of PTGS2 along with genes regulating VEGF signalling pathway and association with high‐risk factors in locally advanced oral squamous cell carcinoma

Prostaglandin-endoperoxide synthase 2 (PTGS2) gene expression and its association with genes regulating the VEGF signaling pathway in head and neck squamous cell carcinoma

Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization

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