Benefits of Multifaceted Chemopreventives in the Suppression of the Oral Squamous Cell Carcinoma (OSCC) Tumorigenic Phenotype

Abstract

Over 1/3 of patients who have undergone oral squamous cell carcinoma (OSCC) surgical resections develop life-threatening and often untreatable recurrences. A variety of drugs, intended for management of recurrent or disseminated cancers, were designed to exploit cancer cells’ reliance upon overexpressed receptors and gratuitous signaling. Despite their conceptual promise, clinical trials showed these agents lacked efficacy and were often toxic. These findings are consistent with evasion of pathway-targeted treatments via extensive signaling redundancies and compensatory mechanisms common to cancers. Optimal secondary OSCC chemoprevention requires long term efficacy with multifaceted, nontoxic agents. Accordingly, this study evaluated the abilities of three complementary chemopreventives i.e. the vitamin A derivative fenretinide (4-HPR, induces apoptosis and differentiation, inhibits signaling proteins and invasion), the estrogen metabolite 2-methoxyestradiol (2-ME, apoptosis-inducing, antiangiogenic) and the humanized monoclonal antibody to the IL-6R receptor tocilizumab (TOC, reduces IL-6 signaling) to suppress OSCC gratuitous signaling and tumorigenesis. Modeling studies demonstrated 4-HPR's high affinity binding at STAT3's dimerization site and c-Abl and c-Src ATP-binding kinase sites. Although individual agents suppressed cancer-promoting pathways including STAT3 phosphorylation, STAT3-DNA binding, and production of the trans-signaling enabling sIL-6R, maximal chemopreventive effects were observed with agent combinations. OSCC tumor xenograft studies showed that locally-delivered TOC, TOC+4-HPR and TOC+4-HPR+2-ME treatments all prevented significant tumor growth. Notably, the TOC+4-HPR+2-ME treatment resulted in the smallest overall increase in tumor volume. The selected agents employ diverse mechanisms to disrupt tumorigenesis at multiple venues i.e. intracellular, tumor cell-ECM and tumor microenvironment; beneficial qualities for secondary chemopreventives.

In vivo controlled release of fenretinide from long-acting release depots for chemoprevention of oral squamous cell carcinoma recurrence

“…Due to low animal numbers statistical analyses were not suitable). The efficacy of 4HPR-PLGA millicylinder in these studies served as proof of concept for more comprehensive studies which showed that 4HPR was effective in combination with other chemotherapeutic agents such as tocilizumab and 2-methoxyestradial at reducing rate of tumor growth (Mallery et al, 2017). Shown in Fig.…”

“…Previous studies from our labs have demonstrated that fenretinide (4HPR) inhibits focal adhesion kinase-extracellular matrix (FAK-ECM) interactions and significantly reduces invasion, which is the ultimate step in OSCC development (Han et al, 2015). To address OSCC’s redundant signaling cascades, secondary OSCC chemoprevention will ultimately require complementary agents (Mallery et al, 2017). Based on 4HPR’s multiple mechanisms of action including growth regulation and suppression of gratuitous signaling, (Han et al, 2015) it is our intention to include 4HPR in the secondary chemopreventive formulation.…”

Role of Key Micronutrients from Nutrigenetic and Nutrigenomic Perspectives in Cancer Prevention

“…Also, nutrients appear to be able to influence different cellular processes [9], some of which are related to tumorigenesis [43]; therefore, one consideration is how certain nutrients have an influence on cancer development or progression [44,45]. Natural nutrients are able to disrupt tumorigenesis at multiple ‘omic’ levels and, concurrently, increase the chemotherapeutic efficacy and reduce the side effects related to these treatments [46]. One of the relevant examples is related to oral cancer, which can be arguably prevented by maintaining good oral hygiene, eliminating the use of tobacco and alcohol products, and by having a balanced healthy diet.…”

Tocilizumab, a Potent Interleukin-6 Receptor Inhibitor, Decreases Bone Resorption and Increases the Rate of Bacterial Infection After Tooth Extraction in Rats

“… 3 Due to its ability to inhibit inflammation, TCZ is being used in the treatment of rheumatoid arthritis, including as monotherapy, and Crohn disease, asthma, and Coleman disease, and as an adjuvant for multiple myeloma, some lymphomas, and solid-organ cancers, including colorectal, breast, prostate, ovarium, pancreas, lung, and kidney cancers. 4 Recently, TCZ has been used as palliative treatment for oral squamous cell carcinomas 5 , 6 and multi-drug-resistant anemia 7 , 8 ; thus, its range of therapeutic applications has increased.…”