Photodynamic therapy using zinc phthalocyanine with low dose of diode laser combined with doxorubicin is a synergistic combination therapy for human SK-MEL-3 melanoma cells
Graphical abstract
Introduction
Malignant Melanoma is the most common aggressive skin cancer worldwide. As reported by the American Cancer Society, about 91,270 new cases of melanoma were approximated to be detected in 2018. About 9,320 Americans are estimated to die from melanoma in 2018 [1]. Heavy prices are spent every year on research in order to treat melanoma or improve the quality of life in patients. The most common strategies of melanoma treatment are surgery, radiation therapy and chemotherapy [2]. Chemotherapy is a commonly used anticancer approach and has been significantly developed to date [3]. Nevertheless, serious side effects and drug-resistance can lead to limited therapeutic outcomes of chemotherapy in most kinds of cancers such as melanoma [[4], [5], [6]]. Owing to the heterogeneity and rapid proliferation of melanoma cells along with the high probability of melanoma invasion and metastasis [5], any single treatment approach is generally not sufficient to destroy the entire tumor [7]. Combination therapy using two or more therapeutic agents either simultaneously or sequentially has been explored since the 1960s, in order to improve the effectiveness of cancer therapy [[8], [9], [10]]. Combination therapy shows better therapeutic results when compared to single therapies, especially in reducing drug-resistance and preventing cancer recurrence. Combination therapy can also decrease side effects and improve the survival rate in cancer patients [7].
The combination of chemotherapy with photodynamic therapy (PDT) has received significant attention as a promising approach to treat cancer [[11], [12], [13]]. PDT is an effective minimally-invasive approach to the treatment of cancers of different types and sites as well as non-cancerous diseases. Excellent therapeutic results and capability of the parallel application of PDT with other treatments make it attractive [14]. PDT is based on local or systemic administration of a photoactive agent (photosensitizer), which is selectively accumulated in the tumor. The photosensitizer molecules absorb light of the specific wavelength and produce reactive oxygen species (ROS) inducing a biological cascade leading to selective death of the targeted cells. In the treatment of melanoma with PDT immediately suggests the question of the interaction of light with endogenous molecules of skin (such as melanin and hemoglobin) which absorb light. The most appropriate wavelength for PDT is 600–800 nm, which is known as the “therapeutic window”. Melanin and hemoglobin exhibit absorption across the visible region of the spectrum, but both fall to a minimum level in the therapeutic window [15,16].
Research over the last decades has shown that the use of two or more therapeutic approach in cancer treatment has more effective results than the single therapy approach. Notwithstanding the success of combined chemotherapy with DOX and ZnPc-PDT (chemo-PDT,) identify the most important factors and innovative methods are yet being researched and needed to improve the effective use of chemo-PDT in clinical oncology. Although PDT and chemotherapy have shown high potential for cancer therapy, both strategies have complex limitations, such as high side effects and drug-resistance (for chemotherapy) and difficulty in the light delivery of some internal tumors (for PDT). Biological mechanisms and effective factors of chemo-PDT effectiveness are extremely intricate and not completely identified to date. In this regard, the purpose of this work are (I) the comparative study of effects of low and high dose of light source in combination ZnPc-PDT with DOX to investigate the role of light source in chemo-PDT synergistic outcomes; (II) the comparative study of cellular and molecular mechanisms after chemo-PDT to highlighting significant results. So, we characterizing these mechanisms aimed at maximizing therapeutic outcomes with minimum invasive effects by employing the advantages of both strategies.
Section snippets
Cell line and cell culture
Human melanoma cell line (SK-MEL-3) was obtained from the Pasteur Institute of Iran. The cells were cultured in Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 10% fetal bovine serum (Gibco, USA) and 1% antibiotics (penicillin /streptomycin, Gibco, USA). Subsequently, cells were incubated in the incubator at 37 °C under an atmosphere of 5% CO2 and 95% humidity.
In vitro cellular uptake of ZnPc
According to our previously reported article [17], DMSO was used to make ZnPc dissolve in the culture medium. The
Results and discussion
The role of the light source used in PDT is highly complex and remarkable. So, characterizing roles of the light source in synergistic effects of combination therapy leads to design better PDT and chemo-PDT protocols that extensively improve these efficiencies. Although the use of chemotherapy and PDT are clinically extended, the mechanisms underlying cancer cells death after chemo-PDT and effective factors are not completely characterized. In fact, one of the main areas of studies in the
Conclusion
Chemotherapy has always played and still play vital roles in melanoma treatment. Chemo-PDT is a powerful combination therapeutic approach with two anticancer strategies (PDT and chemotherapy) that can decrease the rate of metastasis and initiate melanoma cells death.
In 2016, studies by Tahmasebi et al. on melanoma cell line demonstrated that the melanoma cells incubated with 5-Aminolevulinic acid (5-ALA) and 5-fluorouracil(5-FU), enhanced the efficiency of 5-ALA-PDT [41].
In 2018, Gao et al.
Funding
Michael R Hamblin was supported by USNIH grant R01AI050875.
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