Targeting the epigenome in malignant melanoma: Facts, challenges and therapeutic promises

Anestopoulos, Ioannis; Kyriakou, Sotiris; Tragkola, Venetia; Paraskevaidis, Ioannis; Tzika, Eleni; Mitsiogianni, Melina; Deligiorgi, Maria V; Petrakis, G.; Trafalis, Dimitrios T.; Botaitis, Sotirios; Giatromanolaki, Alexandra; Koukourakis, Michael I.; Franco, Rodrigo; Pappa, Aglaia; Panayiotidis, Mihalis Ι.

doi:10.1016/j.pharmthera.2022.108301

Cited by 17 publications

(5 citation statements)

References 379 publications

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“…The mouse weight and tumour growth after implantation were monitored daily. Mice with a tumour volume (TV) of approximately 100 mm 3 were selected for the study. The selected mice were randomly divided into four groups, with six mice in each group.…”

Section: In Vivo Antitumour Efficacy and Safetymentioning

confidence: 99%

“…The prognosis of patients with MM is abysmal, as the 5-year survival rate is 10–15%, and the average median survival time is only 6–9 months. 3 , 4 Research on the pathogenesis of MM has revealed, that MM invasion and metastasis are related to many factors, including gene mutations inherent to MM and the interplay between MM cells and the immune system and microenvironment. 5 , 6 Therefore, immunotherapy and gene therapy have become promising strategies for MMM.…”

Section: Introductionmentioning

confidence: 99%

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Dendritic Cell-Derived Exosomes Driven Drug Co-Delivery Biomimetic Nanosystem for Effective Combination of Malignant Melanoma Immunotherapy and Gene Therapy

Lin¹,

Huang²,

Li³

et al. 2023

DDDT

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Purpose Malignant melanoma (MM), the most lethal skin cancer, is highly invasive and metastatic. These qualities are related to not only genetic mutations in MM itself but also the interaction of MM cells with the immune system and microenvironment. This study aimed to construct a combined immunotherapy and gene therapy drug delivery system for the effective treatment of MM. Methods Mature dendritic cell (mDC) exosomes (mDexos) with immune induction functions were used as carriers. BRAF siRNA (siBRAF) with the ability to silence mutated BRAF in MM was encapsulated in mDexos by electroporation to construct a biomimetic nanosystem for the codelivery of immunotherapy and gene therapy drugs (siBRAF-mDexos) to the MM microenvironment. Then, we investigated the nanosystem’s serum stability and biocompatibility, uptake efficiency in mouse melanoma cells (B16-F10 cells), cytotoxicity against B16-F10 cells and inhibitory effect on BRAF expression. Furthermore, we evaluated its antimelanoma activity and safety in vivo. Results SiBRAF-mDexos were nanosized. Compared to siBRAF, siBRAF-mDexos displayed significantly increased serum stability, biocompatibility, uptake efficiency in B16-F10 cells, and cytotoxicity to B16-F10 melanoma cells; they also had a significantly greater inhibitory effect on BRAF expression and induced T-lymphocyte proliferation. Moreover, compared with siBRAF, siBRAF-mDexos showed significantly enhanced anti-MM activity and a high level of safety in vivo. Conclusion The study suggests that the siBRAF-mDexo biomimetic drug codelivery system can be used to effectively treat MM, which provides a new strategy for combined gene therapy and immunotherapy for MM.

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Section: In Vivo Antitumour Efficacy and Safetymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dendritic Cell-Derived Exosomes Driven Drug Co-Delivery Biomimetic Nanosystem for Effective Combination of Malignant Melanoma Immunotherapy and Gene Therapy

Lin¹,

Huang²,

Li³

et al. 2023

DDDT

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“…Malignant melanoma (MM) is one of the most lethal and aggressive types of skin cancer and is associated with the highest rates of mutation and treatment resistance. It is responsible for the majority of skin-related cancer mortality worldwide, especially in its metastatic form ( Anestopoulos et al, 2022 ; Wagstaff et al, 2022 ). The incidence of melanoma has been increasing worldwide ( Tucker, 2009 ; Carr et al, 2020 ; Forsea, 2020 ; Bolick and Geller, 2021 ; Memon et al, 2021 ; Saginala et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Studies have revealed that BRAF (B-Raf proto-oncogene, serine/threonine kinase), KRAS (Kirsten rat sarcoma), NRAS (neuroblastoma RAS viral oncogene homolog), HRAS (Harvey Rat sarcoma viral oncogene), CDKN2B (Cyclin dependent kinase inhibitor 2B) , PTEN (phosphatase and the tensin homolog deleted on chromosome 10), TERT (telomerase reverse transcriptase), and p53 are the most commonly mutated genes in MM progression, which can potentially cause resistance to targeted therapy. Moreover, BRAF mutations occur in approximately 60.0% of MM cases ( Anestopoulos et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Ferroptosis as a promising therapeutic strategy for melanoma

Ta,

Jiang,

Zhang

et al. 2023

Front. Pharmacol.

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Malignant melanoma (MM) is the most common and deadliest type of skin cancer and is associated with high mortality rates across all races and ethnicities. Although present treatment options combined with surgery provide short-term clinical benefit in patients and early diagnosis of non-metastatic MM significantly increases the probability of survival, no efficacious treatments are available for MM. The etiology and pathogenesis of MM are complex. Acquired drug resistance is associated with a pool prognosis in patients with advanced-stage MM. Thus, these patients require new therapeutic strategies to improve their treatment response and prognosis. Multiple studies have revealed that ferroptosis, a non-apoptotic form of regulated cell death (RCD) characterized by iron dependant lipid peroxidation, can prevent the development of MM. Recent studies have indicated that targeting ferroptosis is a promising treatment strategy for MM. This review article summarizes the core mechanisms underlying the development of ferroptosis in MM cells and its potential role as a therapeutic target in MM. We emphasize the emerging types of small molecules inducing ferroptosis pathways by boosting the antitumor activity of BRAFi and immunotherapy and uncover their beneficial effects to treat MM. We also summarize the application of nanosensitizer-mediated unique dynamic therapeutic strategies and ferroptosis-based nanodrug targeting strategies as therapeutic options for MM. This review suggests that pharmacological induction of ferroptosis may be a potential therapeutic target for MM.

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“…However, the overall survival (OV) is limited in most patients because of the occurrence of therapy resistance due to high melanoma plasticity that induces the activation of alternative survival pathways [8][9][10][11]. In particular, drug treatments can induce genomic and non-genomic modifications that lead to MAPK signaling reactivation and/or AKT pathway sustainment [12]. Therefore, there is an urgent need to find other molecules that have an effect against melanoma, even when used in association with current anti-melanoma drugs.…”

Section: Introductionmentioning

confidence: 99%

Celecoxib, a Non-Steroidal Anti-Inflammatory Drug, Exerts a Toxic Effect on Human Melanoma Cells Grown as 2D and 3D Cell Cultures

Venuta

Nasso

Gisonna

et al. 2023

Life

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Cutaneous melanoma (CM) remains one of the leading causes of tumor mortality due to its high metastatic spread. CM growth is influenced by inflammation regulated by prostaglandins (PGs) whose synthesis is catalyzed by cyclooxygenases (COXs). COX inhibitors, including non-steroidal anti-inflammatory drugs (NSAIDs), can inhibit tumor development and growth. In particular, in vitro experiments have shown that celecoxib, a NSAID, inhibits the growth of some tumor cell lines. However, two-dimensional (2D) cell cultures, used in traditional in vitro anticancer assays, often show poor efficacy due to a lack of an in vivo like cellular environment. Three-dimensional (3D) cell cultures, such as spheroids, are better models because they can mimic the common features displayed by human solid tumors. Hence, in this study, we evaluated the anti-neoplastic potential of celecoxib, in both 2D and 3D cell cultures of A2058 and SAN melanoma cell lines. In particular, celecoxib reduced the cell viability and migratory capability and triggered the apoptosis of melanoma cells grown as 2D cultures. When celecoxib was tested on 3D melanoma cell cultures, the drug exerted an inhibitory effect on cell outgrowth from spheroids and reduced the invasiveness of melanoma cell spheroids into the hydrogel matrix. This work suggests that celecoxib could represent a new potential therapeutic approach in melanoma therapy.

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Targeting the epigenome in malignant melanoma: Facts, challenges and therapeutic promises

Cited by 17 publications

References 379 publications

Dendritic Cell-Derived Exosomes Driven Drug Co-Delivery Biomimetic Nanosystem for Effective Combination of Malignant Melanoma Immunotherapy and Gene Therapy

Dendritic Cell-Derived Exosomes Driven Drug Co-Delivery Biomimetic Nanosystem for Effective Combination of Malignant Melanoma Immunotherapy and Gene Therapy

Ferroptosis as a promising therapeutic strategy for melanoma

Celecoxib, a Non-Steroidal Anti-Inflammatory Drug, Exerts a Toxic Effect on Human Melanoma Cells Grown as 2D and 3D Cell Cultures

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