Current treatment of cutaneous squamous cancer and molecular strategies for its sensitization to new target-based drugs

Franco, Renato; Nicoletti, Gianfranco; Lombardi, Angela; Domenico, Marina Di; Botti, Gerardo; Marino, Federica Zito; Caraglia, Michele

doi:10.1517/14712598.2012.725720

Cited by 13 publications

(13 citation statements)

References 91 publications

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“…However, some tumors have poorly differentiated features (PD-SCCs) and are eventually spindleshaped, these traits being associated with enhanced recurrence and metastasis (1, 3). Currently, advanced and metastatic skin SCCs are mostly treated with radiotherapy or classical chemotherapy, which have limited clinical benefits (4). Furthermore, the mechanisms that control SCC growth and metastasis at different stages of progression remain unclear, limiting the possibilities for targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression

et al. 2016

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Cancer stem-like cells (CSC) play key roles in long-term tumor propagation and metastasis, but their dynamics during disease progression are not understood. Tumor relapse in patients with initially excised skin squamous cell carcinomas (SCC) is characterized by increased metastatic potential, and SCC progression is associated with an expansion of CSC. Here, we used genetically and chemically-induced mouse models of skin SCC to investigate the signaling pathways contributing to CSC function during disease progression. We found that CSC regulatory mechanisms change in advanced SCC, correlating with aggressive tumor growth and enhanced metastasis. b-Catenin and EGFR signaling, induced in early SCC CSC, were downregulated in advanced SCC. Instead, autocrine FGFR1 and PDGFRa signaling, which have not been previously associated with skin SCC CSC, were upregulated in late CSC and promoted tumor growth and metastasis, respectively. Finally, high-grade and recurrent human skin SCC recapitulated the signaling changes observed in advanced mouse SCC. Collectively, our findings suggest a stage-specific switch in CSC regulation during disease progression that could be therapeutically exploited by targeting the PDGFR and FGFR1 pathways to block relapse and metastasis of advanced human skin SCC.

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Section: Introductionmentioning

confidence: 99%

Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression

et al. 2016

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“…Chemotherapy of existing skin tumors may be a less scarring alternative to surgery and provide benefit for those with higher risk of metastasis (15). However, a number of studies have shown that metastatic squamous cell carcinoma (SCC) can resist certain chemotherapies, but become sensitized upon inhibition of specific pathways (15, 16).…”

Section: Introductionmentioning

confidence: 99%

“…However, a number of studies have shown that metastatic squamous cell carcinoma (SCC) can resist certain chemotherapies, but become sensitized upon inhibition of specific pathways (15, 16). In addition, P-gp was found to be upregulated in human SCC tissue and SCC cell lines as compared to epidermis and normal keratinocytes (17).…”

Section: Introductionmentioning

confidence: 99%

Resveratrol and P-glycoprotein Inhibitors Enhance the Anti-Skin Cancer Effects of Ursolic Acid

Junco

Mancha

Malik

et al. 2013

Molecular Cancer Research

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Ursolic acid (UA), present in apples, rosemary, and other sources, is known to inhibit tumor formation and tumor cell viability in multiple systems, including skin. However, various cancers are resistant to UA treatment. Herein, skin carcinoma cells (Ca3/7) as compared to skin papilloma cells (MT1/2) displayed more resistance to UA-induced cytotoxicity. Interestingly, Ca3/7 cells had elevated levels of P-glycoprotein (P-gp), an ATP-dependent efflux pump that mediates resistance to chemotherapy in pre-clinical and clinical settings, and not only accumulated less but also more rapidly expelled the P-gp substrate Rhodamine 123 (Rh123) indicating UA is transported by P-gp. To determine if P-gp inhibition can enhance UA-mediated cytotoxicity, cells were challenged with P-gp inhibitors verapamil (VRP) or cyclosporin A (CsA). Alternatively, cells were pre-treated with the natural compound resveratrol (RES), a known chemotherapy sensitizer. VRP and RES enhanced the effects of UA in both cell lines, while CsA only did so in Ca3/7 cells. Similarly, VRP inhibited Rh123 efflux in both lines, while CsA only inhibited Rh123 efflux in Ca3/7 cells. RES did not inhibit Rh123 efflux in either line, indicating the synergistic effects of RES and UA are not manifest by inhibition of P-gp-mediated efflux of UA. These results indicate that the anti-skin cancer effects of UA are enhanced with P-gp inhibitors. In addition, RES and UA interact synergistically, but not through inhibition of P-gp. Implications Resveratrol and/or p-glycoprotein inhibitors in combination with ursolic acid are an effective anti-skin cancer regimen.

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“…Our hypothesis sought to explore the utility of FA as a novel second-line treatment by testing FA as a single agent and studying its effect on HEp2 and a HEp-Doc cell line [5]. Chemotherapy resistance is an issue of clinical significance in cases of recurrent and second primary HNSCC [12,13,14,15,16]. …”

Section: Discussionmentioning

confidence: 99%

Effects of Fusaric Acid Treatment on HEp2 and Docetaxel-Resistant HEp2 Laryngeal Squamous Cell Carcinoma

Montero

Stack³

2013

Chemotherapy

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Background: Head and neck squamous cell carcinoma (HNSCC) can become resistant to some chemotherapy and becomes a clinical challenge when it recurs. There are few agents identified for second-line treatment of resistant head and neck cancer. Therefore, we evaluated the role of fusaric acid (FA) as a possible agent for treatment for chemotherapy-resistant laryngeal squamous cell carcinoma. Methods: The HEp2 and docetaxel-resistant HEp2 (HEp-Doc) cell lines were created from human laryngeal cancer. Cell lines were exposed to FA at increasing concentrations (0.1, 0.3, and 0.5 mM) and time intervals of 24, 48, 72, and 96 h. The effects on cell survival, apoptosis, and cytokine and protein expression were analyzed. Results: FA treatment in the HEp-Doc cells showed greater reduction of cell number and colony-forming units and more apoptosis when compared to HEp2 and required less time to reduce cell number. Four cytokines were detected in HEp2 cancer cells that increased with FA treatment. Pro-caspase-9 and -7 and poly (ADP-ribose) polymerase also increased with FA treatment. Conclusion: FA may be an agent to be considered in cases of HNSCC treatment resistance or post-docetaxel recurrence. Further investigation of FA in vitro and in vivo is indicated.

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Current treatment of cutaneous squamous cancer and molecular strategies for its sensitization to new target-based drugs

Cited by 13 publications

References 91 publications

Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression

Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression

Resveratrol and P-glycoprotein Inhibitors Enhance the Anti-Skin Cancer Effects of Ursolic Acid

Effects of Fusaric Acid Treatment on HEp2 and Docetaxel-Resistant HEp2 Laryngeal Squamous Cell Carcinoma

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