The effect of combined treatment with cold atmospheric plasma and doxorubicin on melanoma: a critical umbrella systematic review and meta-analysis of experimental studies

doi:10.21203/rs.3.rs-5268466/v1

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The effect of combined treatment with cold atmospheric plasma and doxorubicin on melanoma: a critical umbrella systematic review and meta-analysis of experimental studies

https://doi.org/10.21203/rs.3.rs-5268466/v1

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Objective: Melanoma is responsible for the majority of skin cancer deaths, but there are several ways to combat this deadly disease. One method involves the use of anti-neoplastic agents, such as doxorubicin (DOX). Unfortunately, DOX can be toxic and may lead to drug resistance. However, researchers are excited about the potential of cold atmospheric plasma (CAP) to selectively target cancer cells and overcome drug resistance. To gain a better understanding of the effectiveness of the combination of CAP and DOX on melanoma cell viability, cytotoxicity, and cell death, we conducted a comprehensive evaluation and meta-analysis in this study.

Results: A total of 41 studies out of 121 met our inclusion criteria. Pooled analysis revealed that the CAP and DOX combination had a significant effect on cell viability (ES =6.75, 95% CI: 1.65--11.85, and I2 = 71%) and cytotoxicity (ES =11.71, 95% CI: 3.69--19.73, and I2 = 56%). However, no statistically significant association was found between cell death and thecombination treatment.

Conclusions: Our studies confirmed that combined treatment with CAP and DOX has a synergistic effect on reducing cell viability and increasing cytotoxicity in melanoma cells. These results can assist researchers in selecting more effective treatment methods to address melanoma.

Biological sciences/Cancer

Biological sciences/Cell biology

Biological sciences/Drug discovery

Biological sciences/Immunology

Biological sciences/Molecular biology

Health sciences/Diseases

melanoma

cold atmospheric plasma

doxorubicin

cell viability

cytotoxicity.

In this study, the anticancer effects of different combinations of plasma gas and doxorubicin on different types of melanoma cell lines were investigated.
In the present study, a significant relationship between cell viability and the combination of CAP and DOX was observed in melanoma.
In the present study, a significant relationship between cell cytotoxicity and the combination of CAP and DOX in melanoma was observed.
The results of our studies confirmed the synergistic effect of CAP and DOX combination treatment on the viability and cytotoxicity of melanoma cells.

OPEN QUESTIONS:

Can CAP and DOX treatment have significant anticancer effects on melanoma cells?
Can the use of CAP and DOX significantly affect melanoma cell viability?
Can the use of CAP and DOX treatment have a significant effect on melanoma cell cytotoxicity?
Can the use of CAP and DOX treatment be approved at the cellular level so that it can be used more confidently at the next levels?

Melanoma is a highly aggressive and resistant form of skin cancer that is responsible for the majority of skin cancer-related deaths, although it accounts for only 1% of all cases. Unfortunately, the survival rate of patients with metastatic melanoma is only 27%.[1] Early diagnosis and treatment are crucial for the prognosis and survival of patients with primary melanoma, whose 5-year survival rate is 99%. Treatment for melanoma includes chemotherapy [2], conventional chemotherapy [3], and immune checkpoint inhibitors [4]. Small molecules have been shown to act against mutant BRAF[5]. Tumor heterogeneity limits disease-free survival in patients[6], despite advancements in treatment approaches. Tumor heterogeneity confers varying degrees of resistance and survival advantages. As a result, understanding the biology of tumors is always necessary, as is the development of novel or improved combination therapeutic approaches.

The first line of defense against cancer prevention is provided by a variety of antineoplastic agents[7]. The majority of these agents cause cell cycle arrest and death by targeting or altering deoxyribonucleic acid (DNA) synthesis and repair mechanisms[8]. One of the most potent chemotherapeutic agents, doxorubicin, also known as adriamycin, has significant therapeutic activity against numerous cancers. DOX is an anthracycline that causes DNA damage by intercalating DNA base pairs and inhibiting topoisomerase II activity[9]. However, its use is limited by its toxicity, particularly its cardiotoxicity[10].

In addition, it has been discovered that plasma or a plasma-activated solution also has a good killing effect on drug-resistant cancer cells[11], so CAP is expected to solve drug resistance issues associated with clinical cancer chemotherapy. Recent preliminary studies have confirmed that the combination of a plasma jet with the anticancer drug tegafur can effectively improve the inactivation of pancreatic cancer cells. In addition, the excellent synergistic effects of CAP and anticancer drugs can effectively reduce the number of treatment cycles and the cumulative dose administered from a clinical perspective. Many studies on the use of CAP for cancer therapy have shown that appropriate dosages of CAP can selectively kill cancer cells without causing significant damage to normal cells[12–14]. Numerous reactive oxygen and nitrogen species (ROS/RNS)[15, 16] are produced by cold physical plasma (partially ionized gas), and cells also accumulate ROS; therefore, excess intracellular ROS cause oxidative damage and further induce programmed cell death[17].

However, the extent to which CAP and DOX combination therapy can influence the viability, death, and cytotoxicity of melanoma cells is not known. Meta-analysis is a method used to collect related studies and provide improved statistical power by combining their results. In this study, we aimed to provide a comprehensive systematic review and meta-analysis of subgroup analyses, such as cell line, plasma gas, and treatment time analyses, of melanoma cell viability, death, and cytotoxicity caused by DOX and CAP treatment together or alone.

2.1. Search strategy:

In this systematic review and meta-analysis, the PubMed, Scopus, Web of Science, EMABSE, and Google Scholar electronic databases were searched up to December 2022 via the following search terms: “Melanoma” OR “Malignant Melanoma” OR “Melanoma Malignant” AND “cold atmospheric plasma” OR “Plasma Gases” OR “Gases Plasma” OR “Cold Plasma” OR “Plasma Cold” OR “Nonthermal Atmospheric Pressure Plasma” OR “Thermal Plasma” OR “plasma jet” AND “Doxorubicin” OR “DOX”. All the references cited were manually scanned to find additional studies. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. This study was registered in PROSPERO (PROSPERO ID: CRD42018117203).

2.2. Inclusion and exclusion criteria:

Study selection was performed by two reviewers independently. First, the titles and abstracts of all studies were reviewed to include all the studies on CAP or DOX treatment in patients with melanoma. The full texts of the selected papers were subsequently retrieved to assess and extract the relevant data thoroughly. The inclusion criteria were as follows: in vitro experimental studies; (2) case‒control studies; (3) original articles; (4) English-language papers; (5) sufficient data to calculate the effect size (ES) and 95% CI; (6) melanoma cells from different human or murine lines; and (7) eligible studies to investigate severity, death and cell viability and cytotoxicity, including melanoma cells treated with CAP or DOX or both. (8) Diagnostic methods such as MTT, flow cytometry, and information about death or proliferation and their viability and cytotoxicity should be clearly reported separately by cell type and type of treatment. Studies were excluded if they (1) were nonoriginal publications, including editorials, commentaries, and review articles; (2) were duplicate studies; (3) were animal subjects; or (4) had incomplete information. In vitro experimental studies, (5) case‒control studies, (6) original articles, (7) English-language papers, (8) sufficient data to calculate effect size (ES) and its 95% CI, (9) melanoma cells from different human or murine lines, (10) eligible studies to investigate severity, death and cell viability and cytotoxicity must include melanoma cells treated with CAP or DOX or both, (11) diagnostic methods such as MTT, flow cytometry, and information about death or proliferation and their viability and cytotoxicity should be clearly reported separately by cell type and type of treatment, (12) clinical trial studies, and (13) articles that do not receive the minimum score of the checklist. If the two reviewers could not reach an agreement about the selection of papers, the final decision was made by a third reviewer.

2.3. Data extraction and quality assessment:

Information was carefully extracted from all eligible publications independently by two reviewers according to the inclusion and exclusion criteria. The following information was extracted from each study: article title, author name, country, year of article publication, cell line type, measurement method, gas type, cell life rate, cytotoxicity rate, cell death, treatment time with CAP, dose of drug used, final results and Newcastle‒Ottawa Scale (NOS) score. The quality of the eligible studies was evaluated via the NOS on a 0–9 scale: 0–3 was classified as low-quality, 4–6 as moderate-quality, and ≥ 7 as high-quality. The main characteristics of the included studies are summarized in Table 1.

2.4. Statistical analysis:

The I2 index was used for the assessment of significant heterogeneity between studies. If the test result was I2 ≥ 50%, indicating the presence of heterogeneity, the random-effects model was used; otherwise, the fixed-effects model was selected. We evaluated publication bias via Egger’s regression intercept test (P < 0.05 was considered significant). The meta-analysis was performed with STATA version 11.1 (Stata Corp, College Station, TX, USA).

The PRISMA flow diagram of the study is shown in Fig. 1. We found 129 articles related to the title of this study by search strategy, 8 of which were duplicates and were removed. We screened the titles and abstracts of 121 selected articles for eligibility, and 80 studies were excluded because they did not meet our inclusion and exclusion criteria. Forty-one studies were selected for full-text analysis; after their selection, 1 study was excluded because its data were incomplete or repeated, such as the results of other included articles (the same authors). Finally, 40 case‒control studies were included in the systematic review. Among these selected studies, 20 studies investigated the effect of DOX in melanoma, 17 studies investigated the effect of CAP in the treatment of melanoma, and 3 studies investigated the simultaneous relationship between CAP and DOX in melanoma.

The level of cell viability in these studies was mostly measured via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the degree of cell cytotoxicity was mostly measured via annexin flow cytometry. In these studies, cell death was mostly measured via the assessment of the propidium iodide (PI). Egger’s test did not indicate any evidence of publication bias. All included studies were moderate- to high-quality (14 high-quality studies and 26 moderate-quality studies). The characteristics of the included studies are described in Table 1.

3.1. Main results of the meta-analysis

3.2.1. Meta-analysis of the association between melanoma cell viability and treatment: Pooled analysis of the 25 studies[18-37] investigated the association between melanoma cell viability and CAP treatment. The analysis of the dominant model indicated that a significant association existed between melanoma CAP treatment and decreased melanoma cell viability ([ES] = 58.16, 95% [CI]: 43.59--72.73, I2 = 94.1%). Moreover, 18 studies[28, 38-55] investigated the association between melanoma cell viability and DOX treatment. The analysis of the dominant model indicated that a significant association existed between melanoma DOX treatment and decreased melanoma cell viability ([ES] = 23.96, 95% [CI]: 17.26--13.66, I2 = 86.1%). Six studies[22, 28, 34] investigated the associations between melanoma cell viability and CAP and DOX treatment. The analysis of the dominant model indicated that a significant association existed between melanoma CAP and DOX treatment and decreased melanoma cell viability ([ES] = 6.75, 95% [CI]: 1.65--11.85, I2 = 71%). (Fig. 2)

3.2.2. Meta-analysis of the association between melanoma cell death and treatment:

Seven studies[18, 19, 22-25, 28, 30] evaluated the association between melanoma cell death and CAP treatment. Overall, the results revealed a significant association between melanoma CAP treatment and increased melanoma cell death ([ES] = 3.95, 95% [CI]: 1.59--6.31, I2 = 68.1%). Moreover, in 10 studies[22, 28, 41, 47, 50, 51, 53, 56, 57], the association of melanoma cell death with DOX treatment was evaluated. DOX treatment was significantly associated with increased melanoma cell death ([ES] = 8.17, 95% [CI]: 3.71--12.64, I2 = 84.2%). Pooled analysis of the 3 studies[22, 28] investigated the associations between melanoma cell death and CAP and DOX treatment. The analysis of the dominant model indicated that an association existed between melanoma CAP and DOX treatment and increased melanoma cell death ([ES] = 2.14, 95% [CI]: -0.55--4.84, I2 = 71.0%) (Fig. 3)

3.2.3. Meta-analysis of the association between melanoma cell cytotoxicity and treatment:

In 12 studies[18-20, 22, 27, 28, 30, 33, 37], the association of melanoma cell cytotoxicity with CAP treatment was evaluated. Significant associations were found for CAP treatment and increased melanoma cell cytotoxicity ([ES] = 5.76, 95% [CI]: 2.80--8.73, I2 = 82.8%). In addition, no significant association was found between melanoma cell cytotoxicity and DOX[22, 28, 38, 39] treatment ([ES] = 7.27, 95% [CI]: 3.91--10.64, I2 = 0). Three studies[22, 28] evaluated the associations between melanoma cell cytotoxicity and CAP and DOX treatment. Overall, the results revealed a significant association between melanoma CAP and DOX treatment and increased melanoma cell death ([ES] = 11.71, 95% [CI]: 3.69--19.73, I2 = 56%) (Fig. 4)

Fig. 4. Association between melanoma training and cell cytotoxicity. (A) CAP treatment vs. cell cytotoxicity analysis. (B) DOX treatment vs. cell cytotoxicity analysis. (C) DOX-CAP treatment vs. cell cytotoxicity.

3.2. Subgroup and intragroup analyses:

Due to significant heterogeneity between studies, subgroup analyses were performed. The data related to the subgroup analyses of the studied studies are shown in Table 2). In addition, among the 3 studies that investigated the effects of CAP and DOX and used 5 different types of melanoma, intragroup analyses were performed. The analysis of the dominant model indicated that a significant association existed between melanoma cell viability and CAP treatment ([ES] = 82, 95% [CI]: 72.8--92.29, I2 = 62.7%) or DOX treatment ([ES] = 40.80% [CI]: 19.63--61.97, I2 = 85.6%). Intragroup analyses revealed that CAP treatment ([ES] = 1.21% [CI]: 0.09--2.33, I2 = 39%) and DOX treatment ([ES] = 1.35% [CI]: -3.82--6.52, I2 = 87.4%) are associated with melanoma cell death. Moreover, among the 3 studies, CAP treatment was significantly associated with increased melanoma cell cytotoxicity ([ES] = 1.84% [CI]: -1.14 to 4.09, I2 = 75%) (Figs. 5, 6).

Over the past 30 years, melanoma rates have increased worldwide[58]. Tumor heterogeneity, which refers to the genetic and phenotypic differences between tumor cells, can restrict the disease-free survival period for patients[6]. Despite advancements in cancer treatment, novel combination therapies are often needed. Recently, significant attention has been given to the clinical application of CAP in cancer therapy. [59-61]. The ROS generated by CAP play a significant role in this specific anticancer effect [62-64]. Cancer cells produce large amounts of ROS due to their abnormally active metabolism during rapid proliferation [65]. Injection of only a small dose of CAP generates exogenous reactive species, allowing cancer cells to reach a lethal ROS threshold quickly while normal cells remain unharmed [66]. Additionally, clinical cancer chemotherapy is expected to address drug resistance issues associated with CAP [11]. As a result, CAP and DOX combination therapy is one of the most effective melanoma chemotherapies with a positive impact [10, 58]. It is not yet clear how effectively the combination of CAP and DOX influences the viability, death, and cytotoxicity of melanoma cells. To gain a better understanding of this therapeutic mechanism, we conducted a systematic review and meta-analysis to summarize the effects of CAP and DOX therapy on the viability, cytotoxicity, and death of melanoma cells. The results of previous studies have shown that treating melanoma cells with CAP during tumor treatment reduces cell viability[18, 19, 30]. In addition, previous studies have shown that the use of DOX for the treatment of melanoma is effective and reduces cell viability[38, 39, 44]. The results of our meta-analyses also confirmed this decrease in cell viability with CAP (ES: 58.23) and DOX (ES: 23) treatment alone compared with the control group. The cell viability test results from a previous study also revealed that the combination of CAP and DOX was most effective against cancer[22, 28]. The results of our analyses were also in accordance with those of previous studies and revealed that the viability of the cells in the studies that used the combination of CAP and DOX was significantly lower (ES: 6.75) than that in the studies that used CAP (ES: 58.23) or DOX (ES: 23) alone (Fig. 2). According to the subgroup analysis of cell viability in the A375 cell line subgroup, cell viability was significantly lower in the combined treatment group (ES: 1.20) than in the CAP (ES: 1.54) or DOX (ES: 13.63) group alone. In addition, in the subgroups of the SKMEL28 (ES: 13.52) and B16F0 (ES: 7.90) cell lines, the cell viability was significantly lower with the combined treatment than with the CAP or DOX treatment alone. The results of the treatment-time subgroup analysis indicated that cell viability was significantly lower in the group treated with both CAP and DOX (ES: 1.20) than in the group treated with only DOX (ES: 29.09). Moreover, in the subgroup of the gas used in the CAP device, in the helium gas group, the cell viability in the combined treatment with CAP and DOX was significantly lower (ES: 16.09) than that in the CAP group (ES: 55.50) alone (Table 2). In the intragroup analyses of the studies that used the combined treatment, following our previous analyses, a significant decrease in cell viability was shown with the combined treatment (ES: 6.75) compared with the CAP (ES: 52.54) and DOX (ES: 40.80) treatments alone (Figs. 5, 6).

Previous studies have shown that the use of CAP to treat melanoma has increased cytotoxicity [18, 19, 28]. In addition, previous studies have shown that dox treatment increases cytotoxicity in melanoma cells[22, 28, 38]. Our analysis of cytotoxicity revealed that compared with treatment with CAP (ES: 5.75) or DOX (ES: 7.27) alone, combined treatment with CAP and DOX significantly increased (ES: 11.71) the degree of cytotoxicity (Fig. 4). In addition, in the intragroup analyses of the studies that used the combined treatment, an increase in cytotoxicity was shown for the combined treatment (ES: 11.71) compared with the CAP (ES: 1.48) and DOX (ES: 6.94) treatments, but this increase was not significant (Figs. 5, 6). The results of previous studies, which are consistent with the results of our analysis, revealed an increase in cytotoxicity due to combined treatment with CAP and DOX[22, 28].

Many studies on the use of CAP for cancer therapy have shown that plasma can initiate cell death[18, 19, 28]. Similarly, doxorubicin can also cause increased death in melanoma cancer cells[22, 28, 38]. Moreover, a previous study indicated that combined treatment with CAP and DOX had an increased effect on melanoma cell death[22, 28]. In contrast, our meta-analyses revealed that cell death was reduced by combined treatment, but this reduction was not significant (Fig. 3). However, in the intragroup analysis of the studies that included the combined treatment, cell death increased (ES: 2.14) compared with that in the cap (ES: 1.21) and dox (ES: 1.35) treatment groups. However, this increase was not statistically significant. As a result, it is not possible to provide a firm opinion on this matter (Figs. 5, 6).

In this study, the anticancer effects of different combinations of plasma gas and doxorubicin on different types of melanoma cell lines were investigated. In the present study, a significant relationship between cell viability and cytotoxicity was observed with the combination of CAP and DOX in melanoma. Furthermore, owing to limitations such as high heterogeneity in several of the included studies, probably the result of variation in study design, and relatively small sample sizes, further studies are necessary to understand the effects of combined CAP and DOX treatment on cell death.

To the best of our knowledge, this is the first meta-analysis that examines the effectiveness of combining CAP and DOX in treating melanoma. Compared with the use of either CAP or DOX alone, the combination of CAP and DOX has a marked effect on the viability and cytotoxicity of melanoma cells. This suggests that there is a synergistic effect between the two drugs. These findings can help researchers choose a more appropriate treatment protocol when dealing with melanoma.

· DNA: Deoxyribonucleic acid

· DOX: Doxorubicin

· CAP: Cold Atmospheric Plasma

· ROS/RNS: reactive oxygen and nitrogen species

· NOS: Newcastle‒Ottawa Scale

· MTT: (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)

· PI: (propodium iodide)

Acknowledgment

The authors gratefully acknowledge the student research committee of Mazandaran University of Medical Science, Sari, Iran, for financially supporting this research.

Authors' contributions:

Alireza Rafiei and zeinab rostami designed the study; Reza Alizadeh, Alireza Rafiei, and zeinab rostami. performed the experiments; all authors contributed to the generation of the figures; zeinab rostami. and Reza Alizadeh. wrote the draft; all authors revised the manuscript

Conflict of interest:

The authors declare that they have no conflicts of interest.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: The conducted research is not related to either human or animal use. This is a meta-analysis review article that uses data from other articles that have been approved and published.

Funding:

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Availability of data and materials:

Data is provided within the manuscript or supplementary information files.

*Clinical trial number: not applicable

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The effect of combined treatment with cold atmospheric plasma and doxorubicin on melanoma: a critical umbrella systematic review and meta-analysis of experimental studies

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