Challenges of Systemic Therapy Investigations for Bone Sarcomas

Nakano, Kenji

doi:10.3390/ijms23073540

Cited by 15 publications

(20 citation statements)

References 120 publications

(126 reference statements)

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“…So far, cisplatin based chemotherapy remains the pillar of major osteosarcoma patients. Unfortunately, some patients show prophase platinum resistance, relapse or disease progression after the initial treatment response [23]. Yang et al found that overexpression of Reptin in chemotherapy resistant ovarian cancer and breast cancer can improve DNA damage repair ability, and partially explained its resistance to treatment [24].…”

Section: Discussionmentioning

confidence: 99%

Reptin regulates tumor cell growth and cisplatin resistance in osteosarcoma

Tian

Feng

Liang

et al. 2022

Preprint

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Purpose Osteosarcoma is the most common primary bone tumor with poor prognosis, characterized by high recurrence and metastasis. Recent studies show that Reptin is overexpressed in several malignant tumors and is required for tumorigenesis. Reptin is thought to be involved in chromatin remodeling and DNA damage repair. However, the biological function and the molecular mechanism of Reptin in osteosarcoma are still not fully understood. Methods The expression of Reptin was detected in 59 osteosarcoma and 35 non-neoplastic bone specimens by immunohistochemistry. Kaplan -Meier curves was used to evaluate the prognostic significance of Reptin. Then we knockdown the expression of Reptin in Saos-2 and U2OS cells. MTT, Edu assay, flow cytometry, wound-healing and transwell assays were performed to examine the influences of Reptin expression on cell proliferation, cell cycle, migration and invasion. We further conducted co-immunoprecipitation experiments to explore the relationship between Reptin and DNA-PKcs. Finally, we determined the role of Reptin on DNA damage repair and chemosensitivity of cisplatin. Results We verified that high expression of Reptin was closely associated with tumor differentiation, Enneking stage and metastasis. Patients with Reptin-positive staining exhibited a significantly decreased overall survival. Additionally, we found that Reptin deleption inhibited the proliferation, invasion of osteosarcoma cells and caused G1 arrest. Furthermore, we discovered that Reptin participate in DNA damage repair through interaction with DNA-PKcs, inhibition of Reptin expression in osteosarcoma cells enhances cisplatin sensitivity by aggravating DNA damage. Conclusions In summary, we revealed that Reptin plays a crucial role in tumor growth and may serve as an attractive therapeutic target for osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

Reptin regulates tumor cell growth and cisplatin resistance in osteosarcoma

Tian

Feng

Liang

et al. 2022

Preprint

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“…Osteosarcoma (OS) is the most common primary malignant bone tumor, and represents the second leading cause of cancer-related death in children and adolescents [ 1 , 2 ]. Surgery combined with multimodal chemotherapy, comprising doxorubicin, methotrexate and cisplatin (CDDP), is the standard treatment for OS patients [ 3 , 4 ]. CDDP, an alkylating agent, functions in a cell-cycle-independent manner to cause DNA damage and cell death through alkylated DNA adducts [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Curcumol Synergizes with Cisplatin in Osteosarcoma by Inhibiting M2-like Polarization of Tumor-Associated Macrophages

et al. 2022

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Osteosarcoma is the most prevalent bone cancer, and chemotherapy is still an indispensable treatment in its clinical practice. Cisplatin (CDDP) has become the most commonly used agent for osteosarcoma, although the outcomes of CDDP chemotherapy remain unsatisfactory because of frequent resistance. Here, we report on a promising combination therapy where curcumol, a bioactive sesquiterpenoid, enhanced CDDP-induced apoptosis to eradicate osteosarcoma cells, and revealed that M2-like macrophages might be the underlying associated mechanisms. First, we observed that curcumol enhanced the CDDP-mediated inhibition of cell proliferation and augmented the apoptosis in osteosarcoma cell lines. Curcumol contributed to preventing the migration of osteosarcoma cells when combined with CDDP. Moreover, this drug combination showed more potent tumor-growth suppression in the orthotopic transplantation of osteosarcoma K7M2 WT cells. We then estimated chemotherapy-associated drug-resistant genes, including ABCB1, ABCC1 and ABCG2, and found that curcumol significantly reversed the mRNA levels of CDDP-induced ABCB1, ABCC1 and ABCG2 genes in the tumor tissue. Moreover, M2-like macrophages were enriched in osteosarcoma tissues, and were largely decreased after curcumol and CDDP treatment. Taken together, these findings suggest that curcumol inhibits the polarization of M2-like macrophages and could be a promising combination strategy to synergize with CDDP in the osteosarcoma.

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“…Sarcoma include both slow-growing tumors and highly malignant histological subtypes requiring a multimodal therapy regimen [ 2 , 3 ]. These interdisciplinary treatment concepts include surgery, radiotherapy, and systemic cancer therapy, as well as, in selected cases, regional hyperthermia [ 3 , 4 , 5 , 6 , 7 , 8 ]. In sarcoma, systemic chemotherapy-based treatment still plays a central role in patients with both curative and palliative disease [ 4 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…In sarcoma, systemic chemotherapy-based treatment still plays a central role in patients with both curative and palliative disease [ 4 , 8 ]. Regarding the clinical data existing so far, anthracyclines alone or in combination with the alkylating agent ifosfamide are most commonly used [ 4 , 7 ]. Further treatment options such as trabectedin, eribulin, pazopanib, gemcitabine-based combinations, doxorubicin, cisplatin, etoposide, vincristine, and methotrexate depend on the primary histology, patient age, and comorbidities [ 7 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Regarding the clinical data existing so far, anthracyclines alone or in combination with the alkylating agent ifosfamide are most commonly used [ 4 , 7 ]. Further treatment options such as trabectedin, eribulin, pazopanib, gemcitabine-based combinations, doxorubicin, cisplatin, etoposide, vincristine, and methotrexate depend on the primary histology, patient age, and comorbidities [ 7 , 9 , 10 , 11 , 12 ]. Novel chemotherapy-free approaches including epigenetic regulation via inhibition of the enhancer of zeste homolog 2 (EZH2) with tazemeostat in epithelioid sarcoma, mouse double minute 2 homolog (MDM2) inhibitors, cyclin-dependent kinase (CDK) 4/6 inhibitors or multi-kinase inhibitors, and Poly(ADP-ribose) polymerase (PARP) inhibitors are part of clinical trials or are preserved for specific sarcoma subtypes so far [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Inflammatory Surrogate Parameters for Predicting Ifosfamide-Induced Neurotoxicity in Sarcoma Patients

Schmidt

Benzler

Lauer

et al. 2022

JCM

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Sarcomas compromise a heterogenous group of tumors of a mesenchymal origin. Although treatment options in many solid tumors have evolved over the past decades, the treatment of advanced sarcoma is still based on conventional chemotherapeutic agents. Beside anthracyclines, alkylating agents such as ifosfamide are frequently used in sarcoma treatment. However, treatment with ifosfamide can cause severe dose- and treatment-limiting side effects, such as ifosfamide-induced neurotoxicity (IIN). Especially in sarcoma, consecutive risk assessment analyses investigating the individual factors associated with the increased incidence in IIN, remain insufficient so far. In this retrospective analysis, we investigated 172 sarcoma patients treated with ifosfamide. Out of 172 patients, 49 patients (28.5%) developed IIN. While gender, age, histologic origin, and tumor stage were not associated with the occurrence of IIN, infusion times, simultaneous radiotherapy, and concomitant use of opioids or anticonvulsants affected the risk of developing IIN. Sarcoma patients with IIN showed an alteration in several inflammatory markers, including a lower lymphocyte count, hemoglobin levels, and calcium levels, as well as elevated GGT, sodium, and CRP levels. Remarkably, the occurrence of IIN was associated with a worse prognosis regarding progression free and overall survival. In addition, high CTCAE grades were negatively associated with overall survival in sarcoma. The observation that an inflammatory state is associated with an increased risk of IIN in sarcoma patients can be used prospectively to further investigate the relationship of inflammation and IIN. In addition, the easily accessible blood markers used in our study to predict IIN can be incorporated into clinical decision making.

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Challenges of Systemic Therapy Investigations for Bone Sarcomas

Cited by 15 publications

References 120 publications

Reptin regulates tumor cell growth and cisplatin resistance in osteosarcoma

Reptin regulates tumor cell growth and cisplatin resistance in osteosarcoma

Curcumol Synergizes with Cisplatin in Osteosarcoma by Inhibiting M2-like Polarization of Tumor-Associated Macrophages

Inflammatory Surrogate Parameters for Predicting Ifosfamide-Induced Neurotoxicity in Sarcoma Patients

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