Doxorubicin-Resistant Osteosarcoma: Novel Therapeutic Approaches in Sight?

Hattinger, Claudia Maria; Fanelli, Marilù; Tavanti, Elisa; Vella, Serena; Riganti, Chiara; Picci, Piero; Serra, Massimo

doi:10.2217/fon-2016-0519

Cited by 30 publications

(31 citation statements)

References 27 publications

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“…For IC 50 , OS cells were seeded 5 × 10 3 onto a 96-well plate and treated for 24 h with the nanoformulations. According to the OS cells’ kinetics of growth [ 51 ], WST-1 was performed according to the manufacturer’s protocol after 48 h (MG63 and U2-OS) and 5 days (SaOS-2) from loading. The IC 50 value was calculated by applying a sigmoidal dose response function on the results of three independent experiments in GraphPad PRISM software (vs 6, GraphPad Software, La Jolla, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Functionalized Keratin as Nanotechnology-Based Drug Delivery System for the Pharmacological Treatment of Osteosarcoma

Martella

Ferroni

Guerrini

et al. 2018

IJMS

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Osteosarcoma therapy might be moving toward nanotechnology-based drug delivery systems to reduce the cytotoxicity of antineoplastic drugs and improve their pharmacokinetics. In this paper, we present, for the first time, an extensive chemical and in vitro characterization of dual-loaded photo- and chemo-active keratin nanoparticles as a novel drug delivery system to treat osteosarcoma. The nanoparticles are prepared from high molecular weight and hydrosoluble keratin, suitably functionalized with the photosensitizer Chlorin-e6 (Ce6) and then loaded with the chemotherapeutic drug Paclitaxel (PTX). This multi-modal PTX-Ce6@Ker nanoformulation is prepared by both drug-induced aggregation and desolvation methods, and a comprehensive physicochemical characterization is performed. PTX-Ce6@Ker efficacy is tested on osteosarcoma tumor cell lines, including chemo-resistant cells, using 2D and 3D model systems. The single and combined contributions of PTX and Ce6 is evaluated, and results show that PTX retains its activity while being vehiculated through keratin. Moreover, PTX and Ce6 act in an additive manner, demonstrating that the combination of the cytostatic blockage of PTX and the oxidative damage of ROS upon light irradiation have a far superior effect compared to singularly administered PTX or Ce6. Our findings provide the proof of principle for the development of a novel, nanotechnology-based drug delivery system for the treatment of osteosarcoma.

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Section: Methodsmentioning

confidence: 99%

Functionalized Keratin as Nanotechnology-Based Drug Delivery System for the Pharmacological Treatment of Osteosarcoma

Martella

Ferroni

Guerrini

et al. 2018

IJMS

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“…GSH was assayed via the reaction with 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB) and measured at 412 nm. Evidence indicates that the risk of the occurrence of many tumors is associated with blood lipid profile [high-level total cholesterol (TC), glycerol, and low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels] (Hattinger et al, 2017 ; Ray et al, 2017 ). Thus, the lipid profile, which may be related to OS risk, was measured, including total triglycerides (TGs), TC, HDL-C, and LDL-C using a biochemical analyzer (Dimension, Schererville, IN, USA).…”

Section: Methodsmentioning

confidence: 99%

“…OS has high morbidity and mortality. Moreover, the use of chemotherapy (cisplatin; Chen, 2017 ; Sun et al, 2017 ), doxorubicin (Hattinger et al, 2017 ; Zhang et al, 2017 ), and methotrexate (Valle et al, 2016 ; Ray et al, 2017 ) results in marginal improvement in survival rate even after surgery. The most serious problem is that survival rates have changed little over the past decades because no new drug is available.…”

Section: Introductionmentioning

confidence: 99%

Alginate Oligosaccharide DP5 Exhibits Antitumor Effects in Osteosarcoma Patients following Surgery

et al. 2017

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Osteosarcoma is a malignant musculoskeletal tumor that has high-rate morbidity and mortality worldwide. Alginate oligosaccharide (AOS), a natural product, has antitumor activities and may have therapeutic effects in osteosarcoma, the molecular mechanisms of which remain unclear. AOS was prepared from alginate sodium using alginate lyase. The fractions of AOS were further isolated by size-exclusion chromatography and verified by electrospray ionization mass spectrometry (ESI-MS). Osteosarcoma patients were enrolled in the study and assigned into two groups: AOS (AG, oral administration of 10-mg AOS daily) and control groups (CG, placebo). Preoperative and postoperative clinical data were investigated and analyzed. Four different degrees of polymerizations (DPs) were isolated and denominated as DP2, DP3, DP4, and DP5. Among these polymers, only DP5 showed antitumor functions on osteosarcoma cells. Before surgery and the outcome of primary end point after surgery, no significant differences were observed for clinical data and tumor size between the AG and CG groups (P > 0.05). After 2-year therapy, the mean tumor volume was 214.6 ± 145.7 c.c. in AG and 467.2 ± 225.3 c.c in CG (P < 0.01). The rate of local recurrence was 44.9 and 68.7% in AG and CG, respectively (P < 0.01). AOS treatment resulted in the increase in serum levels of SOD, GSH, HDL-C, and reduction in the levels of interleukin-1 (IL-1) beta and IL-6; the ratios of AST/ALT; and triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol LDL-C, and malondialdehyde (MDA) (P < 0.05). AOS reduces osteosarcoma progression, which is associated with improvement in antioxidant and anti-inflammatory capacities of patients, and may be used as a potential drug for osteosarcoma therapy.

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“…One of the most active drugs for OS treatment is doxorubicin which is invariably included in OS chemotherapy protocols. Several studies have shown that high grade osteosarcoma patients may be inherently resistant to doxorubicin or become un-responsive to this drug during chemotherapy [25]. So, it is urgent to explore the combination regimen with complementary molecular mechanisms to reduce the side effects and enhance sensitivity of Doxorubicin.…”

Section: Disscussionmentioning

confidence: 99%

SOX2OT variant 7 contributes to the synergistic interaction between EGCG and Doxorubicin to kill osteosarcoma via autophagy and stemness inhibition

Wang

Chen

Zhu

2018

J Exp Clin Cancer Res

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Background: Doxorubicin is the preferred chemotherapeuticdrug for osteosarcoma treatment of which clinical efficacy is limited because of its chemo-resistance and cardiac toxicity. It is necessary to develop the combination regimen with complementary molecular mechanisms to reduce the side effects and enhance sensitivity of Doxorubicin. EGCG is a polyphenol in green tea with antitumor bioactivity,which has been found that its combination with certain chemotherapeutic drugs could improve the antitumor efficiency. Methods: In this study, MTT assay was used to detect the cell growth inhibition The CD133+/CD44+ cells were isolated from U2OS and SaoS2 cell lines using magnetic-activated cell sorting and identified by flow cytometry analysis. qRT-PCR was used for determining the relative mRNA levels of key genes. Immunofluorescence was performed to evaluate the autophagy flux alterations. Self-renewal ability was accessed by sphere-forming assay. Tumorigenicity in nude mice was preformed to evaluate tumorigenicity in vivo. Results: We found that EGCG targeting LncRNA SOX2OT variant 7 produced synergistic effects with Doxorubicin on osteosarcoma cell growth inhibition. On the one hand, EGCG could reduce the Doxorubicin-induced pro-survival autophagy through decreasing SOX2OT variant 7 to improve the growth inhibition of Doxorubicin. On the other hand, EGCG could partially inactivate Notch3/DLL3 signaling cascade targeting SOX2OT variant 7 to reduce the stemness then abated drug-resistance of osteosarcoma cells.

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Doxorubicin-Resistant Osteosarcoma: Novel Therapeutic Approaches in Sight?

Cited by 30 publications

References 27 publications

Functionalized Keratin as Nanotechnology-Based Drug Delivery System for the Pharmacological Treatment of Osteosarcoma

Functionalized Keratin as Nanotechnology-Based Drug Delivery System for the Pharmacological Treatment of Osteosarcoma

Alginate Oligosaccharide DP5 Exhibits Antitumor Effects in Osteosarcoma Patients following Surgery

SOX2OT variant 7 contributes to the synergistic interaction between EGCG and Doxorubicin to kill osteosarcoma via autophagy and stemness inhibition

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