Identification of Synergistic, Clinically Achievable, Combination Therapies for Osteosarcoma

Yu, Diana; Kahen, Elliot; Cubitt, Christopher L.; McGuire, Jeremy; Kreahling, Jenny; Lee, Jae Hyuk; Altiok, Soner; Lynch, Conor C.; Sullivan, Daniel M.; Reed, Damon R.

doi:10.1038/srep16991

Cited by 48 publications

(50 citation statements)

References 58 publications

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“…As mentioned above, a handful of studies have documented the ability of bortezomib to kill human osteosarcoma cells, [11][12][13][14] however their sensitivity to newer proteasome inhibitors was not previously investigated. We therefore exposed cells from 2 established human osteosarcoma cell lines (SaOS2 and SJSA1) and 2 in vivo-passaged human lines (OS9 and OS17) to the same panel of proteasome inhibitors that we tested on the canine cells.…”

Section: Discussionmentioning

confidence: 99%

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Patatsos

Shekhar

Hawkins

2018

Vet Comparative Oncology

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Osteosarcoma, a common malignancy in large dog breeds, typically metastasises from long bones to lungs and is usually fatal within 1 to 2 years of diagnosis. Better therapies are needed for canine patients and their human counterparts, a third of whom die within 5 years of diagnosis. We compared the in vitro sensitivity of canine osteosarcoma cells derived from 4 tumours to the currently used chemotherapy drugs doxorubicin and carboplatin, and 4 new anti-cancer drugs. Agents targeting histone deacetylases or PARP were ineffective. Two of the 4 cell lines were somewhat sensitive to the BH3-mimetic navitoclax. The proteasome inhibitor bortezomib potently induced caspase-dependent apoptosis, at concentrations substantially lower than levels detected in the bones and lungs of treated rodents. Co-treatment with bortezomib and either doxorubicin or carboplatin was more toxic to canine osteosarcoma cells than each agent alone. Newer proteasome inhibitors carfilzomib, ixazomib, oprozomib and delanzomib manifested similar activities to bortezomib. Human osteosarcoma cells were as sensitive to bortezomib as the canine cells, but slightly less sensitive to the newer drugs. Human osteoblasts were less sensitive to proteasome inhibition than osteosarcoma cells, but physiologically relevant concentrations were toxic. Such toxicity, if replicated in vivo, may impair bone growth and strength in adolescent human osteosarcoma patients, but may be tolerated by canine patients, which are usually diagnosed later in life. Proteasome inhibitors such as bortezomib may be useful for treating canine osteosarcoma, and ultimately may improve outcomes for human patients if their osteoblasts survive exposure in vivo, or if osteoblast toxicity can be managed.

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Section: Discussionmentioning

confidence: 99%

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Patatsos

Shekhar

Hawkins

2018

Vet Comparative Oncology

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“…To quantify the synergistic effect of the synthesized CS-SeNPs, we used the Chou-Talalay method 15 specifically designed for drug combination. This theory uses algorithms developed by CompuSyn software 13 to demonstrate synergy, additivity, or antagonism, as shown in the fraction affected (Fa)-CI plot 57 ( Figure 3C). We analyzed the dose-effect parameters of each compound alone (CS and SeNPs) as well as in combination, and thus obtained the CI value.…”

Section: Discussionmentioning

confidence: 99%

Synergistic antifungal effect of chitosan-stabilized selenium nanoparticles synthesized by pulsed laser ablation in liquids against <em>Candida albicans</em> biofilms

Lara¹,

Guisbiers²,

Mendoza³

et al. 2018

IJN

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BackgroundCandida albicans is a major opportunistic fungal pathogen. One of the most important virulence factors that contribute to the pathogenesis of candidiasis is its ability to form biofilms. A key characteristic of Candida biofilms is their resistance to antifungal agents. Due to significant morbidity and mortality rates related to biofilm-associated drug resistance, there is an urgency to develop novel nanotechnology-based approaches preventing biofilm-related infections.MethodsIn this study, we report, for the first time, the synthesis of selenium nanoparticles by irradiating selenium pellets by nanosecond pulsed laser ablation in liquid chitosan as a capping agent. Synergy of the fungicidal effect of selenium nanoparticles and chitosan was quantified by the combination index theorem of Chou–Talalay.ResultsThis drug combination resulted in a potent fungicidal effect against a preformed C. albicans biofilm in a dose–response manner. By advanced electron microscopy techniques, we documented the adhesive and permeabilizing properties of chitosan, therefore allowing selenium nanoparticles to enter as the cell wall of the yeast became disrupted and distorted. Most importantly, we demonstrated a potent quantitative synergistic effect when compounds such as selenium and chitosan are combined.ConclusionThese chitosan-stabilized selenium nanoparticles could be used for ex vivo applications such as sterilizers for surfaces and biomedical devices.

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“…Osteosarcoma is a common malignant bone tumor, which is predominant in childhood and adolescence [1]. Multidrug chemotherapy and surgical removal of primary tumors have shown ameliorating effects [2]. Although improvements in therapeutic strategies have been achieved, the prognosis remains poor for most patients with recurrent osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

The lncRNAs RP1-261G23.7, RP11-69E11.4 and SATB2-AS1 are a novel clinical signature for predicting recurrent osteosarcoma

et al. 2020

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Background: Osteosarcoma is the most common primary bone malignancy in children and adolescents. In order to find factors related to its recurrence, and thus improve recovery prospects, a powerful clinical signature is needed. Long noncoding RNAs (lncRNAs) are essential in osteosarcoma processes and development, and here we report significant lncRNAs to aid in earlier diagnosis of osteosarcoma. Methods: A univariate Cox proportional hazards regression analysis and a multivariate Cox regression analysis were used to analyze osteosarcoma patients’ lncRNA expression data from the Therapeutically Applicable Research To Generate Effective Treatments (TARGET), a public database. Results: A lncRNA signature consisting of three lncRNAs (RP1-261G23.7, RP11-69E11.4 and SATB2-AS1) was selected. The signature was used to sort patients into high-risk and low-risk groups with meaningful recurrence rates (median recurrence time 16.80 vs. >128.22 months, log-rank test, P<0.001) in the training group, and predictive ability was validated in a test dataset (median 16.32 vs. >143.80 months, log-rank test, P=0.006). A multivariate Cox regression analysis showed that the significant lncRNA was an independent prognostic factor for osteosarcoma patients. Functional analysis suggests that these lncRNAs were related to the PI3K-Akt signaling pathway, the Wnt signaling pathway, and the G-protein coupled receptor signaling pathway, all of which have various, important roles in osteosarcoma development. The significant 3-lncRNA set could be a novel prediction biomarker that could aid in treatment and also predict the likelihood of recurrence of osteosarcoma in patients.

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Identification of Synergistic, Clinically Achievable, Combination Therapies for Osteosarcoma

Cited by 48 publications

References 58 publications

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Synergistic antifungal effect of chitosan-stabilized selenium nanoparticles synthesized by pulsed laser ablation in liquids against <em>Candida albicans</em> biofilms

The lncRNAs RP1-261G23.7, RP11-69E11.4 and SATB2-AS1 are a novel clinical signature for predicting recurrent osteosarcoma

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