             Send Orders for Reprints to reprints@benthamscience.ae 5540 Current Medicinal Chemistry, 2018, 25, 5540-5563 REVIEW ARTICLE Photodynamic Therapy in Melanoma - Where do we Stand? Ioana Baldea 1,* , Lorin Giurgiu 1 , Ioana Diana Teacoe 1 , Diana Elena Olteanu 1,* , Florin Catalin Olteanu 2 , Simona Clichici 1 and Gabriela Adriana Filip 1 1 Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania; 2 Industrial Engineering and Management Department, Transylvania University, Brasov, Romania A R T I C L E H I S T O R Y Received: March 09, 2017 Revised: November 21, 2017 Accepted: November 29, 2017 DOI: 10.2174/0929867325666171226115626 Abstract: Background: Malignant melanoma is one of the most aggressive malignant tu- mors, with unpredictable evolution. Despite numerous therapeutic options, like chemother- apy, BRAF inhibitors and immunotherapy, advanced melanoma prognosis remains severe. Photodynamic therapy (PDT) has been successfully used as the first line or palliative ther- apy for the treatment of lung, esophageal, bladder, non melanoma skin and head and neck cancers. However, classical PDT has shown some drawbacks that limit its clinical applica- tion in melanoma. Objective: The most important challenge is to overcome melanoma resistance, due to mela- nosomal trapping, presence of melanin, enhanced oxidative stress defense, defects in the apoptotic pathways, immune evasion, neoangiogenesis stimulation. Method: In this review we considered: (1) main signaling molecular pathways deregulated in melanoma as potential targets for personalized therapy, including PDT, (2) results of the clinical studies regarding PDT of melanoma, especially advanced metastatic stage, (3) pro- gresses made in the design of anti-melanoma photosensitizers (4) inhibition of tumor neoan- giogenesis, as well as (5) advantages of the derived therapies like photothermal therapy, sonodynamic therapy. Results: PDT represents a promising alternative palliative treatment for advanced melanoma patients, mainly due to its minimal invasive character and low side effects. Efficient mela- noma PDT requires: (1) improved, tumor targeted, NIR absorbing photosensitizers, capable of inducing high amounts of different ROS inside tumor and vasculature cells, possibly al- lowing a theranostic approach; (2) an efficient adjuvant immune therapy. Conclusion: Combination of PDT with immune stimulation might be the key to overcome the melanoma resistance and to obtain better, sustainable clinical results. Keywords: Photodynamic therapy, melanoma, photosensitizer, neoangiogenesis, immune therapy, oxidative stress, signaling pathway. 1. INTRODUCTION Photodynamic therapy (PDT) is a minimally inva- sive two-stage procedure that requires prior administra- tion of a photosensitizing agent (PS) followed by acti- vation with light of suitable wavelengths. This gener- ates singlet oxygen (1O 2 ) and other highly cytotoxic reactive oxygen species (ROS) [1-3], leading to a *Address correspondence to this author at the Universitatea de Medicina si Farmacie Iuliu Hatieganu Ringgold standard institution - Physiology Cluj-Napoca Romania Cluj-Napoca, Romania; E-mail: baldeaioana@gmail.com combination of direct tumor cell photodamage, destruc- tion of tumor vasculature and activation of an immune response [4, 5], both at treatment site and at distance. The PDT induced immune response was involved in long lasting tumor regression, resistance to rechallenge with viable tumor cells or even cures, on in vivo mod- els [4]. Malignant melanoma is one of the most aggressive malignant tumors with unpredictable evolution. Moreover, the frequency of melanomas is rising and the onset age has diminished. Melanoma is a cancer of the melanocytes, pigmented cells, involved in skin 1875-533X/18 $58.00+.00 © 2018 Bentham Science Publishers