Hyperthermia Enhances Doxorubicin Therapeutic Efficacy against A375 and MNT-1 Melanoma Cells

Salvador, Diana; Bastos, Verónica; Oliveira, Helena

doi:10.3390/ijms23010035

Cited by 12 publications

(9 citation statements)

References 88 publications

(98 reference statements)

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“…Altogether, these results indicate that oxidative stress was increased in the melanoma microenvironment by the combined sequential therapy without triggering compensatory antioxidant protective mechanisms in tumor cells. The overall pro-oxidant state might be attributed to the reported cytotoxic effects of DOX which are induced by generation of reactive oxygen species in targeted cells ( Asensio-López et al, 2017 ; Salvador and Bastos, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…DOX cytotoxic effects are induced by inner mitochondrial membrane localization and ROS production which enhances intracellular toxicity ( Montalvo et al, 2020 ). In melanoma, DOX is reported to induce cell cycle arrest, oxidative stress, and apoptosis if administered in combination with other factors that overcome intrinsic DOX resistance ( Licarete et al, 2020 ; Salvador and Bastos, 2021 ). Therefore, we next investigated the effects of the targeted sequential therapy consisting of IL-13-LCL-SIM and PEG-EV-DOX on oxidative stress parameters and apoptotic status in the TME.…”

Section: Discussionmentioning

confidence: 99%

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Active Tumor-Targeting Nano-formulations Containing Simvastatin and Doxorubicin Inhibit Melanoma Growth and Angiogenesis

et al. 2022

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Primary melanoma aggressiveness is determined by rapid selection and growth of cellular clones resistant to conventional treatments, resulting in metastasis and recurrence. In addition, a reprogrammed tumor-immune microenvironment supports melanoma progression and response to therapy. There is an urgent need to develop selective and specific drug delivery strategies for modulating the interaction between cancer cells and immune cells within the tumor microenvironment. This study proposes a novel combination therapy consisting of sequential administration of simvastatin incorporated in IL-13-functionalized long-circulating liposomes (IL-13-LCL-SIM) and doxorubicin encapsulated into PEG-coated extracellular vesicles (PEG-EV-DOX) to selectively target both tumor-associated macrophages and melanoma cells. To this end, IL-13 was conjugated to LCL-SIM which was obtained via the lipid film hydration method. EVs enriched from melanoma cells were passively loaded with doxorubicin. The cellular uptake of rhodamine-tagged nano-particles and the antiproliferative potential of the treatments by using the ELISA BrdU-colorimetric immunoassay were investigated in vitro. Subsequently, the therapeutic agents were administered i.v in B16.F10 melanoma-bearing mice, and tumor size was monitored during treatment. The molecular mechanisms of antitumor activity were investigated using angiogenic and inflammatory protein arrays and western blot analysis of invasion (HIF-1) and apoptosis markers (Bcl-xL and Bax). Quantification of oxidative stress marker malondialdehyde (MDA) was determined by HPLC. Immunohistochemical staining of angiogenic markers CD31 and VEGF and of pan-macrophage marker F4/80 was performed to validate our findings. The in vitro data showed that IL-13-functionalized LCL were preferentially taken up by tumor-associated macrophages and indicated that sequential administration of IL-13-LCL-SIM and PEG-EV-DOX had the strongest antiproliferative effect on tumor cells co-cultured with tumor-associated macrophages (TAMs). Accordingly, strong inhibition of tumor growth in the group treated with the sequential combination therapy was reported in vivo. Our data suggested that the antitumor action of the combined treatment was exerted through strong inhibition of several pro-angiogenic factors (VEGF, bFGF, and CD31) and oxidative stress-induced upregulation of pro-apoptotic protein Bax. This novel drug delivery strategy based on combined active targeting of both cancer cells and immune cells was able to induce a potent antitumor effect by disruption of the reciprocal interactions between TAMs and melanoma cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Active Tumor-Targeting Nano-formulations Containing Simvastatin and Doxorubicin Inhibit Melanoma Growth and Angiogenesis

et al. 2022

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“…Mantso and colleagues [ 28 ] also exposed A375 cells to 43 °C for 2 h and to DTIC (5, 10, 30 μM) for 24–72 h. The results are similar to ours, showing that exposing cells to DTIC in combination with hyperthermia had a significantly potentiated effect on reducing cell viability at 48–72 h post-exposure, while at 24 h no significant changes were observed [ 28 ]. In our previous work with A375 and MNT-1 cells, we also observed that the potentiated effect of doxorubicin by hyperthermia was dependent on the drug concentration and heat period, demonstrating that not all combined drug and hyperthermia treatments are efficient [ 21 ]. Considering our results and with the aim of using a low DTIC concentration and small heating period with a significantly enhanced effect, an exposure time of 30 min to hyperthermia and 48 h to IC20 (5.5 μg/mL to A375 and 115 μg/mL to MNT-1) were selected to the following experiments.…”

Section: Discussionmentioning

confidence: 99%

“…Combinatorial treatments have been showing promising results in melanoma treatment, from which can be highlighted hyperthermia and immunotherapy [ 63 ], radiotherapy and immunotherapy [ 64 ], and hyperthermia combined with chemotherapy [ 21 ]. Here, we demonstrated that combining hyperthermia with DTIC can be a promising alternative to apply in a primary or metastatic melanoma treatment, as shown by A375 and MNT-1 cells, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its benefits when used alone, hyperthermia is usually applied in combination with other therapies, from which radiotherapy and chemotherapy can be highlighted [ 20 ]. In fact, hyperthermia is known to sensitize cancer cells to chemotherapeutic DNA damaging agents [ 21 , 22 , 23 ]. However, both normal and cancer cells have efficient DNA repair mechanisms that offer protection against therapeutic drugs [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Combined Therapy with Dacarbazine and Hyperthermia Induces Cytotoxicity in A375 and MNT-1 Melanoma Cells

Salvador¹,

Bastos²,

Oliveira³

2022

IJMS

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Melanoma is a drug-resistant cancer, representing a serious challenge in cancer treatment. Dacarbazine (DTIC) is the standard drug in metastatic melanoma treatment, despite the poor results. Hyperthermia has been proven to potentiate chemotherapy. Hence, this work analyzed the combined action of hyperthermia and DTIC on A375 and MNT-1 cell lines. First, temperatures between 40 °C and 45 °C were tested. The effect of DTIC on cell viability was also investigated after exposures of 24, 48, and 72 h. Then, cells were exposed to 43 °C and to the respective DTIC IC10 or IC20 of each time exposure. Overall, hyperthermia reduced cell viability, however, 45 °C caused an excessive cell death (>90%). Combinational treatment revealed that hyperthermia potentiates DTIC’s effect, but it is dependent on the concentration and temperature used. Also, it has different mechanisms from the treatments alone, delaying A375 cells at the G2/M phase and MNT-1 cells at the S and G2/M phases. Intracellular reactive oxygen species (ROS) levels increased after treatment with hyperthermia, but the combined treatment showed no additional differences. Also, hyperthermia highly increased the number of A375 early apoptotic cells. These results suggest that combining hyperthermia and DTIC should be more explored to improve melanoma treatment.

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Implantable smart hyperthermia nanofibers for cancer therapy: Challenges and opportunities

Valizadeh

Asghari

Abbaspoor

et al. 2023

WIREs Nanomed Nanobiotechnol

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Nanofibers (NFs) with practical drug‐loading capacities, high stability, and controllable release have caught the attention of investigators due to their potential applications in on‐demand drug delivery devices. Developing novel and efficient multidisciplinary management of locoregional cancer treatment through the design of smart NF‐based systems integrated with combined chemotherapy and hyperthermia could provide stronger therapeutic advantages. On the other hand, implanting directly at the tumor area is a remarkable benefit of hyperthermia NF‐based drug delivery approaches. Hence, implantable smart hyperthermia NFs might be very hopeful for tumor treatment in the future and provide new avenues for developing highly efficient localized drug delivery systems. Indeed, features of the smart NFs lead to the construction of a reversibly flexible nanostructure that enables hyperthermia and facile switchable release of antitumor agents to eradicate cancer cells. Accordingly, this study covers recent updates on applications of implantable smart hyperthermia NFs regarding their current scope and future outlook.This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants

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Hyperthermia Enhances Doxorubicin Therapeutic Efficacy against A375 and MNT-1 Melanoma Cells

Cited by 12 publications

References 88 publications

Active Tumor-Targeting Nano-formulations Containing Simvastatin and Doxorubicin Inhibit Melanoma Growth and Angiogenesis

Active Tumor-Targeting Nano-formulations Containing Simvastatin and Doxorubicin Inhibit Melanoma Growth and Angiogenesis

Combined Therapy with Dacarbazine and Hyperthermia Induces Cytotoxicity in A375 and MNT-1 Melanoma Cells

Implantable smart hyperthermia nanofibers for cancer therapy: Challenges and opportunities

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