Polyurea Dendrimer Folate-Targeted Nanodelivery of l-Buthionine Sulfoximine as a Tool to Tackle Ovarian Cancer Chemoresistance

Cruz, Adriana; Mota, Pedro; Ramos, Cristiano; Pires, Rita F.; Mendes, Cindy; Silva, José P; Nunes, Sónia; Bonifácio, Vasco D. B.; Serpa, Jacinta

doi:10.3390/antiox9020133

Cited by 28 publications

(12 citation statements)

References 41 publications

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“…Previous studies have reported that the combination of Ce6 and BSO via polymer nanoparticles significantly enhances the effect of photodynamic therapy and inhibits cancer progression compared to therapy without BSO. In ovarian cancer, BSO sensitizes cancer cells to carboplatin therapy via utilizing folate-targeted polyuria dendrimer nanoparticles, which simultaneously decrease the cytotoxicity to normal cells . These studies indicate that the combination of BSO and traditional chemotherapy drugs via nanodrug delivery systems is an effective method for cancer therapy.…”

Section: Discussionmentioning

confidence: 92%

“…In ovarian cancer, BSO sensitizes cancer cells to carboplatin therapy via utilizing folate-targeted polyuria dendrimer nanoparticles, which simultaneously decrease the cytotoxicity to normal cells. 42 These studies indicate that the combination of BSO and traditional chemotherapy drugs via nanodrug delivery systems is an effective method for cancer therapy. Pt/BSO-MS-HA not only consumed GSH by releasing DSCP but also suppressed the synthesis of GSH by BSO in our study.…”

Section: ■ Discussionmentioning

confidence: 99%

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Nanoporous Silica Nanoparticles Coloaded with Cisplatin Prodrug and l-Buthionine Sulfoximine for Cancer Therapy

Xiao

et al. 2023

ACS Appl. Nano Mater.

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Intracellular glutathione (GSH) is critical for cisplatin-resistant cancers by maintaining the redox balance. Amplifying the intracellular oxidative stress by disrupting the redox balance is an effective method for the treatment of cancers. Therefore, we design a mesoporous silica (MS) nanosystem coated by hyaluronic acid (HA) to codeliver l-buthionine sulfoximine (BSO) and cisplatin prodrug (DSCP) (defined as Pt/BSO-MS-HA). The intracellular GSH could react with DSCP in Pt/BSO-MS-HA, which could release free cisplatin for chemotherapy, and the BSO block the synthesis of GSH, leading to GSH depletion and disrupting the redox balance. Moreover, HA provides homotypic binding capacities and superior immune evasion, which significantly enhance the cell uptake of Pt/BSO-MS-HA and tumor accumulation. In in vivo studies, Pt/BSO-MS-HA could efficiently inhibit tumor growth and showed no obvious side effects. Our study provides an effective strategy to develop biocompatible drug delivery nanosystem by disrupting the redox balance in cancer cells, which significantly increase the therapeutic efficiency of cancer chemotherapy.

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Section: Discussionmentioning

confidence: 92%

Section: ■ Discussionmentioning

confidence: 99%

Nanoporous Silica Nanoparticles Coloaded with Cisplatin Prodrug and l-Buthionine Sulfoximine for Cancer Therapy

Xiao

et al. 2023

ACS Appl. Nano Mater.

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“…In liver cancer, SSA was reported to inhibit CD133-positive HCC cells and sensitize HCC cells towards chemotherapy [ 37 ]. Furthermore, the direct ablation of GSH synthesis by BSO has also been demonstrated to exert therapeutic effects in various types of cancer cells [ 38 , 39 ]. In this study, we demonstrated that depletion of GSH and cysteine by BSO and SSA in HCC cells could partially suppress the aggressive phenotypes induced by GSH and NAC.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant supplements promote tumor formation and growth and confer drug resistance in hepatocellular carcinoma by reducing intracellular ROS and induction of TMBIM1

et al. 2021

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Background Controversy over the benefits of antioxidants supplements in cancers persists for long. Using hepatocellular carcinoma (HCC) as a model, we investigated the effects of exogenous antioxidants N-acetylcysteine (NAC) and glutathione (GSH) on tumor formation and growth. Methods Multiple mouse models, including diethylnitrosamine (DEN)-induced and Trp53KO/C-MycOE-induced HCC models, mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection were used. In vitro assays including ROS assay, colony formation, sphere formation, proliferation, migration and invasion, apoptosis, cell cycle assays were conducted. Western blot was performed for protein expression and RNA-sequencing to identify potential gene targets. Results In these multiple different mouse and cell line models, we observed that NAC and GSH promoted HCC tumor formation and growth, accompanied with significant reduction of intracellular reactive oxygen species (ROS) levels. Moreover, NAC and GSH promoted cancer stemness, and abrogated the tumor-suppressive effects of Sorafenib both in vitro and in vivo. Exogenous supplementation of NAC or GSH reduced the expression of NRF2 and GCLC, suggesting the NRF2/GCLC-related antioxidant production pathway might be desensitized. Using transcriptomic analysis to identify potential gene targets, we found that TMBIM1 was significantly upregulated upon NAC and GSH treatment. Both TCGA and in-house RNA-sequence databases showed that TMBIM1 was overexpressed in HCC tumors. Stable knockdown of TMBIM1 increased the intracellular ROS; it also abolished the promoting effects of the antioxidants in HCC cells. On the other hand, BSO and SSA, inhibitors targeting NAC and GSH metabolism respectively, partially abrogated the pro-oncogenic effects induced by NAC and GSH in vitro and in vivo. Conclusions Our data implicate that exogenous antioxidants NAC and GSH, by reducing the intracellular ROS levels and inducing TMBIM expression, promoted HCC formation and tumor growth, and counteracted the therapeutic effect of Sorafenib. Our study provides scientific insight regarding the use of exogenous antioxidant supplements in cancers.

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“…In order to overcome this limitation, interesting studies have been carried out using polymeric nanoparticles loaded with BSO and other anticancer agents [Cruz A, Mota P et al 2020].…”

Section: Gsh Biosynthesis Inhibitorsmentioning

confidence: 99%

Glutathione in cancer progression and chemoresistance: an update

Valenti

Tasso

Traverso

et al. 2023

Redox Experimental Medicine

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Glutathione is one of the most important components of the cellular antioxidant system and it is able to exert several pleiotropic functions influencing cell growth, proliferation, adaptation and death. It has been demonstrated that changes in glutathione levels underlie the pathogenesis of many human diseases, including cancer. In detail, although on one hand glutathione homeostasis plays a protective role from the onset of cancer, on the other, it is involved in cancer progression and in therapy resistance. Objective: In this review, after a brief report on the physiological role of glutathione, we have focused the attention on its role in cancer and refractoriness to anticancer therapy giving an update on the preclinical and clinical studies relied on the compounds targeting glutathione system. Conclusions and significance: Based on these considerations, a deeper knowledge of glutathione-dependent network can be crucial to identify new strategies for preventing and/or curing cancer.

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Polyurea Dendrimer Folate-Targeted Nanodelivery of l-Buthionine Sulfoximine as a Tool to Tackle Ovarian Cancer Chemoresistance

Cited by 28 publications

References 41 publications

Nanoporous Silica Nanoparticles Coloaded with Cisplatin Prodrug and l-Buthionine Sulfoximine for Cancer Therapy

Nanoporous Silica Nanoparticles Coloaded with Cisplatin Prodrug and l-Buthionine Sulfoximine for Cancer Therapy

Antioxidant supplements promote tumor formation and growth and confer drug resistance in hepatocellular carcinoma by reducing intracellular ROS and induction of TMBIM1

Glutathione in cancer progression and chemoresistance: an update

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