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ABSTRACTLittle is known about the effect of enzyme replacement therapy (ERT) on the bone abnormalities in Gaucher disease. Splenectomized Gaucher patients tend to suffer the most severe skeletal complications. We hypothesized that vitamin D supplementation would act synergistically with glucocerebrosidase infusions to increase bone density in splenectomized Gaucher patients. In a 24-month study, 29 splenectomized Gaucher patients were randomized to three groups: Group 1, calcitriol (1,25-dihydroxyvitamin D3; 0.25–3.0 μg/day) alone for the first 6 months with the addition of ceredase/cerezyme at 60 IU/kg every 2 weeks during months 7–12; Group 2, calcitriol together with ceredase/cerezyme at 60 IU/kg every 2 weeks during months 1–6; and Group 3, enzyme only at 60 IU/kg body wt every 2 weeks. In all three groups, enzyme dose was halved after the first 6 months of therapy. The primary outcome measure was bone mineral density of the lumbar spine measured by single-energy quantitative CT. Bone density by single-energy CT (P = 0.001) and by dual-energy CT (P = 0.06) declined overall, but there was no significant difference between the groups. Calcitriol had no significant effect on bone density. Fat fraction in lumbar spine increased (P = 0.000) and skeletal MRI scores improved. Bone-specific alkaline phosphatase (P = 0.002) and serum osteocalcin increased (P = 0.008), while blood cyclic AMP and urinary deoxypyridinoline did not change appreciably. Hemoglobin, platelet counts, and liver volume significantly improved. We conclude that ERT alone, or in combination with calcitriol, cannot repair the bone composition in splenectomized adult Gaucher patients. Alternatively, measuring trabecular bone density may be an inadequate marker of clinical efficacy for treating skeletal involvement in Gaucher disease. [Copyright &y& Elsevier]

Discusses Gaucher's disease, an autosomal genetic disorder classified as a lipid lyosomal storage disease. Pathophysiology; Signs and symptoms; Complications; Types of Gaucher's disease; Systemic manifestations of the disease.

Describes the case of a patient who experienced discomfort and limitation in the left hip and pelvis. Case history; Results of physical examination and radiographs; Cycles of postoperative chemotherapy received by the patient.

ABSTRACT: Chordomas are rare bone tumors and treatment is commonly based on a combination of surgery and radiotherapy. There is no standard chemotherapy treatment for chordoma. The aim of this study was to determine the expression of cyclin‐dependent kinase 4 (CDK4) in chordoma and its therapeutic implications. We evaluated CDK4 expression both in chordoma cell lines and in chordoma tissues. Also, we investigated the functional roles of CDK4 in chordoma cell growth and proliferation. Furthermore, the therapeutic implications of targeting CDK4 in chordoma were evaluated. We found CDK4 highly expressed in chordoma cell lines and in a majority (97.7%) of chordoma tissues. Higher CDK4 expression correlated with metastasis and recurrence of chordoma. Treatment of chordoma cells using CDK4 inhibitor palbociclib could efficiently inhibit chordoma cells growth and proliferation. These data demonstrate that targeting CDK4 may be useful as a novel strategy in the treatment of chordoma. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1581–1589, 2018. [ABSTRACT FROM AUTHOR]

The article presents the author's comments about the article "Treatment of Deep Cartilage Defects in the Knee With Autologous Chondrocyte Transplantation," by M. Brittberg, A. Lindahl, A. Nilsson, C. Ohlsson, O. Isaksson and L. Peterson in the present issue of the "New England Journal of Medicine." According to the author, Brittberg and associates show that autologous chondrocytes lead to the growth of material resembling normal cartilage on being introduced into a knee cartilage defect.

The article presents some of the advances in the treatment of malignant musculoskeletal tumors that were reported from August 2013 through October 2014. An overview about chondrosarcoma, which remains a surgically treated disease, is provided. Also tackled are some developments on primary bone tumors which include chordoma, osteosarcoma and soft-tissue sarcoma.

Background: Lymphoma of bone is uncommon. As a result of this, many aspects of primary lymphoma of bone (PLB) are controversial: the definition, treatment strategies, response criteria, and prognostic factors. Questions/purposes: We sought to determine the following in an analysis from a single center over a four-decade period: (1) 5-year disease-free survival of patients with PLB as well as those with systemic lymphoma with bone involvement; and (2) whether prognostic factors (sex, site of tumor, age) were associated with 5-year survival. Methods: A total of 119 patients with lymphoma involving the musculoskeletal system were retrospectively evaluated. Among these, 94 patients who had a minimum followup of 6 months (mean, 67 months; range, 6 months to 34 years) were further analyzed for the skeletal site of involvement, the orthopaedic intervention(s) needed, and survival. The overall median age was 45 years (range, 7-87 years). The female-to-male ratio was 1:1.53. There were 70 (65 unifocal, five multifocal) patients with PLB. The femur was the most frequent site involved. Appendicular skeleton involvement was substantially higher in patients with PLB. Thirty-four (36%) patients had at least one surgical intervention. Fourteen patients (41%) needed more than one major surgical intervention. Results: The disease-free 5-year survival for patients with PLB was 81% and for the patients with systemic lymphoma with bone involvement, it was 44%. The disease-free 5-year survival of the patients with PLB younger than 60 years old and 60 years old or older was 90% and 62%, respectively. Age was the only prognostic factor on survival of patients with PLB. Conclusions: Orthopaedic intervention was usually needed for pathologic fractures, avascular necrosis, spinal cord compression, or for the lesions of the weightbearing bones compromising stability or joint motion. The potential for long-term survival suggests the use of implants and techniques that have the best chance of long-term success. Level of Evidence: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

The article presents a case study of a forty-seven-year-old man with a two-year history of right shoulder pain and generalized should discomfort. In this context, the authors describe a unique case of synovial chondromatosis in the shoulder following multiple recurrences with a repeatedly benign histologic appearance. However, abnormal results on deoxyribonucleic acid flow cytometry ultimately demonstrated histologic evidence of malignant transformation.

Presents a case report of multiple myeloma with a pathologic fracture during pregnancy in the U.S. Production of lytic bone lesions throughout the skeleton as the result of a monoclonal proliferation of plasma cells that invade the medullary space and activate osteoclasts; Consideration of bone pain as the most common symptom of myeloma; Clinical manifestations of the disease.

Background/Aims: Drug resistance is the main difficulty for the current treatment for osteosarcoma. Cluster of differentiation 44 (CD44) is a receptor for hyaluronic acid (HA) and HA-binding has been proven to participate in various biological tumor activities, including tumor progression, metastasis and drug resistance. In this study, we aimed to determine the effects of CD44 on migration, invasion, proliferation, and the drug-sensitivity of osteosarcoma. Methods: 96 human osteosarcoma tissues from 56 patients were collected to evaluate the expression of CD44 in osteosarcoma tissue by immunohistochemistry. CRISPR-Cas9 system was used to specifically silence CD44 in drug-resistant cell lines (KHOSR2 and U-2OSR2). The migration and invasion activities of cells was demonstrated by wound healing and transwell invasion assay. The proliferation speed of the cells was detected under 3D cell culture condition. Drug resistance of cells was detected by MTT and drug uptake assay. Results: The immunohistochemistry results demonstrated that a high level of CD44 may predict poor survival and higher potential of metastasis, recurrence and drug resistance in patients with osteosarcoma. After knocking-out of CD44 by the CRISPR-Cas9 system, not only the migration and invasion activities of osteosarcoma cells were significantly inhibited, but the drug sensitivity was also enhanced. Conclusion: CD44 silencing could inhibit the development of osteosarcoma migration, invasion, proliferation and ameliorate drug resistance to current treatment in osteosarcoma. This study applies new strategy to target CD44, which may improve the prognosis of osteosarcoma. [ABSTRACT FROM AUTHOR]

Background/Aims: Metastasis is the major cause of death in patients with osteosarcoma. There is an urgent need to identify molecular markers that promote metastasis. Cluster of differentiation 44 is a receptor for hyaluronic acid (HA) and HA-binding has been proven to participate in various biological tumor activities, including tumor progression and metastasis. Methods: We performed a meta-analysis to investigate the relationship between CD44 expression, survival, and metastasis in patients with osteosarcoma. We then utilized the CRISPR-Cas9 system to specifically silence CD44 in highly metastatic human osteosarcoma cells (MNNG/HOS and 143B) and further determined the functional effects of CD44 knockout in these cells. Results: The meta-analysis demonstrated that a high level of CD44 may predict poor survival and higher potential of metastasis in patients with osteosarcoma. The expression of CD44 in highly metastatic human osteosarcoma cell lines was efficiently blocked by CRISPR-Cas9. When CD44 was silenced, the proliferation and spheroid formation of these osteosarcoma cells was inhibited under 3-D culture conditions. Furthermore, the migratory and invasive functions were also impaired in these highly metastatic osteosarcoma cells. Conclusion: These results suggest that developing new strategies to target CD44 in osteosarcoma may prevent metastasis and improve the clinical outcome of osteosarcoma patients. [ABSTRACT FROM AUTHOR]

Purpose: Overexpression of cyclin-dependent kinase (CDK) 4 has been observed in a variety of cancers and has been found to contribute to tumor cell growth and proliferation. However, the effect of inhibition of CDK4 in ovarian cancer is unknown. We investigated the therapeutic effect of the CDK4 inhibitor palbociclib in combination with paclitaxel in ovarian cancer cells. Methods: Cell viabilities were determined by MTT assay after exposure to different dosages of palbociclib and/or paclitaxel. Western blot, immunofluorescence, and Calcein AM assays were conducted to determine the mechanisms underlying the cytotoxic effects of palbociclib in combination with paclitaxel. CDK4 siRNA was used to validate the outcome of targeting CDK4 by palbociclib in ovarian cancer cells. Results: We found that combinations of palbociclib and paclitaxel significantly enhanced drug sensitivity in both Rb-positive (SKOV3TR) and Rb-negative (OVCAR8TR) ovarian cancer-derived cells. When combined with paclitaxel, palbociclib induced apoptosis in both SKOV3TR and OVCAR8TR cells. We also found that palbociclib inhibited the activity of P-glycoprotein (Pgp), and that siRNA-mediated CDK4 knockdown sensitized multidrug resistant (MDR) SKOV3TR and OVCAR8TR cells to paclitaxel. Conclusions: Inhibition of CDK4 by palbociclib can enhance paclitaxel sensitivity in both Rb-positive and Rb-negative MDR ovarian cancer cells by increasing apoptosis. CDK4 may serve as a promising target in the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

ABSTRACT Survival of osteosarcoma patients is currently limited by the development of metastases and multidrug resistance (MDR). A well-established cause of MDR involves overexpression of P-glycoprotein (Pgp) in tumor cells. However, some discrepancies still exist as to the clinical significance of Pgp in osteosarcoma. We sought to elucidate further whether the Pgp expression correlated with clinical behavior in a series of patients with osteosarcoma via high-throughput tissue microarray (TMA) analysis. Immunohistochemical analysis of Pgp expression in a TMA of 114 specimens with a retrospective review of 70 osteosarcoma patients admitted to the Massachusetts General Hospital (MGH) was performed. High Pgp expression was correlated with metastasis development and poor response to pre-operative chemotherapy in osteosarcoma patients. Eighteen of the fifty-seven patients initially admitted with primary osteosarcoma showed high Pgp expression. Among these 18 patients with high Pgp expression, 13 of 18 (72%) patients eventually developed metastases. There was no significant clinical relevance between Pgp expression and osteosarcoma survival. These results support that high expression of Pgp is important, but cannot be assigned as, an individual predictor in the development of human osteosarcoma. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1606-1612, 2016. [ABSTRACT FROM AUTHOR]

ABSTRACT Osteosarcoma is the most prevalent histological form of primary malignant bone tumor. The majority of osteosarcoma patients have limited alternative therapeutic options and metastatic patients generally have a poor prognosis. Proto-oncogene serine/threonine-protein kinase PIM1 is associated with growth and survival of many kinds of tumor cells. However, the role of PIM1 in osteosarcoma remains largely unknown. In this study, we investigated the functional and therapeutic relevance of PIM1 as a putative target in osteosarcoma. We found PIM1 was highly expressed in various osteosarcoma cell lines and in tumor tissues from osteosarcoma patients. Tissue microarray and immunohistochemistry analysis showed that the overall and disease-free survival rate of patients with high levels of PIM1 protein expression were significantly shorter than patients with low levels. High levels of PIM1 were also associated with present metastasis and can be considered as an independent prognostic factor in osteosarcoma patients. Knockdown of PIM1 expression by synthetic siRNA or shRNA greatly inhibited cell growth, migration, and invasion. Moreover, these changes accompanied with down-regulation of anti-apoptotic protein Bcl-2. The similar results were obtained in osteosarcoma cells treated with PIM1 specific inhibitor (SMI-4a). These results suggest that PIM1 kinase is critical for the growth and metastasis of osteosarcoma cells and can be a potential therapeutic target for osteosarcoma treatment. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1185-1194, 2016. [ABSTRACT FROM AUTHOR]

Purpose: Multidrug resistance (MDR) is a major obstacle to the successful treatment of osteosarcoma with chemotherapy. Effectiveness of cancer therapy correlates with the ability to induce a p53-dependent apoptotic response. p53 is a tumor suppressor gene that is mutated in 22 % of osteosarcomas. While impaired p53 has been implicated in the oncogenesis of osteosarcoma, it is unclear whether overexpression of wild-type p53 can increase chemosensitivity in MDR osteosarcoma cells.Methods: We transfected a plasmid encoding the wild-type p53 gene to MDR osteosarcoma cell lines, which have different p53 statuses, U-2OSR2 with wild-type p53 (Wt-p53) and KHOSR2 with mutant p53 (Mt-p53), and determined the effect of p53 overexpression on chemosensitivities.Results: Both of the U-2OSR2 and KHOSR2 cell lines displayed similar trends in p53-induced drug sensitivities. However, it seems that the impact of p53 overexpression is different based on the differential intrinsic p53 status in these cell lines. In the KHOSR2 cell line (Mt-p53), overexpression of p53 up-regulates the expression of pro-apoptotic protein p21 and Bax, while in the U-2OSR2 cell line (Wt-p53), overexpression of p53 down-regulates IGF-1r expression significantly.Conclusions: These results demonstrated that transfection of wild-type p53 increases chemosensitivity either through inhibiting IGF-1r or through increasing the expression of pro-apoptotic proteins p21 and Bax in human MDR osteosarcoma cell lines. [ABSTRACT FROM AUTHOR]

Background and Purpose: Increased expression of P-glycoprotein (PGP1) is one of the major causes of multidrug resistance (MDR) in cancer, including in osteosarcoma, which eventually leads to the failure of cancer chemotherapy. Thus, there is an urgent need to develop effective therapeutic strategies to override the expression and function of PGP1 to counter MDR in cancer patients.Experimental Approach: In an effort to search for new chemical entities targeting PGP1-associated MDR in osteosarcoma, we screened a 500+ compound library of known kinase inhibitors with established kinase selectivity profiles. We aimed to discover potential drug synergistic effects among kinase inhibitors and general chemotherapeutics by combining inhibitors with chemotherapy drugs such as doxorubicin and paclitaxel. The human osteosarcoma MDR cell lines U2OSR2 and KHOSR2 were used for the initial screen and secondary mechanistic studies.Key Results: After screening 500+ kinase inhibitors, we identified NVP-TAE684 as the most effective MDR reversing agent. NVP-TAE684 significantly reversed chemoresistance when used in combination with doxorubicin, paclitaxel, docetaxel, vincristine, ET-743 or mitoxantrone. NVP-TAE684 itself is not a PGP1 substrate competitive inhibitor, but it can increase the intracellular accumulation of PGP1 substrates in PGP1-overexpressing cell lines. NVP-TAE684 was found to inhibit the function of PGP1 by stimulating PGP1 ATPase activity, a phenomenon reported for other PGP1 inhibitors.Conclusions and Implications: The application of NVP-TAE684 to restore sensitivity of osteosarcoma MDR cells to the cytotoxic effects of chemotherapeutics will be useful for further study of PGP1-mediated MDR in human cancer and may ultimately benefit cancer patients. [ABSTRACT FROM AUTHOR]

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. The two major histological subtypes of RMS are alveolar RMS, driven by the fusion protein PAX3-FKHR or PAX7-FKHR, and embryonic RMS, which is usually genetically heterogeneous. The prognosis of RMS has improved in the past several decades due to multidisciplinary care. However, in recent years, the treatment of patients with metastatic or refractory RMS has reached a plateau. Thus, to improve the survival rate of RMS patients and their overall well-being, further understanding of the molecular and cellular biology of RMS and identification of novel therapeutic targets are imperative. In this review, we describe the most recent discoveries in the molecular and cellular biology of RMS, including alterations in oncogenic pathways, miRNA (miR), in vivo models, stem cells, and important signal transduction cascades implicated in the development and progression of RMS. Furthermore, we discuss novel potential targeted therapies that may improve the current treatment of RMS. [ABSTRACT FROM AUTHOR]

Objective The development of multidrug resistance (MDR) remains the significant clinical challenge in ovarian cancer therapy; however, relatively little is known about how to prevent the emergence of MDR during chemotherapy treatment. NSC23925 previously has been shown to prevent the development of MDR in osteosarcoma cells in vitro. The purpose of this study was to evaluate the effects of NSC23925 on the prevention of MDR in ovarian cancer, especially in vivo. Methods Human ovarian cancer cells were treated with paclitaxel alone or in combination with NSC23925 in vitro and in vivo. MDR ovarian cancer cells were established both in cultured cells and mouse models. The expression levels of Pgp and MDR1 were evaluated in various selected cell sublines by Western blot and real-time PCR. Pgp activity was also determined. Results Paclitaxel treated cells eventually developed MDR with overexpression of Pgp and MDR1, and with high activity of Pgp, while paclitaxel-NSC23925 co-treated cells remained sensitive to chemotherapeutic agents in both in vitro and in vivo models. There was no observed increase in expression level and activity of Pgp in paclitaxel-NSC23925 co-treated cells. Additionally, there were no changes in the sensitivity to chemotherapeutic agents, nor expression of Pgp, in cells cultured with NSC23925. Conclusion Our findings suggest that NSC23925 can prevent the emergence of MDR in ovarian cancer both in vitro and in vivo. The clinical use of NSC2395 at the onset of chemotherapy may prevent the development of MDR and improve the clinical outcome of patients with ovarian cancer. [ABSTRACT FROM AUTHOR]

ABSTRACT Osteosarcoma is the most common type primary malignant tumor of bone. Patients with regional osteosarcoma are routinely treated with surgery and chemotherapy. In addition, many patients with metastatic or recurrent osteosarcoma show poor prognosis with current chemotherapy agents. Therefore, it is important to improve the general condition and the overall survival rate of patients with osteosarcoma by identifying novel therapeutic strategies. Recent studies have revealed that CDK11 is essential in osteosarcoma cell growth and survival by inhibiting CDK11 mRNA expression with RNAi. Here, we apply the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 system, a robust and highly efficient novel genome editing tool, to determine the effect of targeting endogenous CDK11 gene at the DNA level in osteosarcoma cell lines. We show that CDK11 can be efficiently silenced by CRISPR-Cas9. Inhibition of CDK11 is associated with decreased cell proliferation and viability, and induces cell death in osteosarcoma cell lines KHOS and U-2OS. Furthermore, the migration and invasion activities are also markedly reduced by CDK11 knockout. These results demonstrate that CRISPR-Cas9 system is a useful tool for the modification of endogenous CDK11 gene expression, and CRISPR-Cas9 targeted CDK11 knockout may be a promising therapeutic regimen for the treatment of osteosarcoma. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:199-207, 2015. [ABSTRACT FROM AUTHOR]

Background: Reversing multidrug resistance (MDR) has been an important goal for clinical and investigational oncologists. In the last few decades, significant effort has been made to search for inhibitors to reverse MDR by targeting ATP-binding cassette (ABC) transporters (Pgp, MRP) directly, but these efforts have achieved little clinical success. Protein kinases play important roles in many aspects of tumor cell growth and survival. Combinations of kinase inhibitors and chemotherapeutics have been observed to overcome cancer drug resistance in certain circumstances. Methods: We screened a kinase specific inhibitor compound library in human osteosarcoma MDR cell lines to identify inhibitors that were capable of reversing chemoresistance to doxorubicin and paclitaxel. Results: We identified 18 small molecules that significantly increase chemotherapy drug-induced cell death in human osteosarcoma MDR cell lines U-2OSMR and KHOSR2. We identified A-770041 as one of the most effective MDR reversing agents when combined with doxorubicin or paclitaxel. A-770041 is a potent Src family kinase (Lck and Src) inhibitor. Western blot analysis revealed A-770041 inhibits both Src and Lck activation and expression. Inhibition of Src expression in U-2OSMR and KHOSR2 cell lines using lentiviral shRNA also resulted in increased doxorubicin and paclitaxel drug sensitivity. A-770041 increases the intracellular drug accumulation as demonstrated by calcein AM assay. Conclusions: These results indicate that small molecule inhibitor A-770041 may function to reverse ABCB1/Pgp-mediated chemotherapy drug resistance. Combination of Src family kinase inhibitor with regular chemotherapy drug could be clinically effective in MDR osteosarcoma. [ABSTRACT FROM AUTHOR]

ABSTRACT Recent studies have revealed that expression of miRNA-1 (miR-1) is frequently down-regulated in several cancer types including chordoma. Identifying and validating novel targets of miR-1 is useful for understanding the roles of miR-1 in chordoma. We aimed to further investigate the functions of miR-1 in chordoma. Specifically, we assessed whether restoration of miR-1 affects cell migration and invasion in chordoma, and focused on the miR-1 potential target Slug gene. Migratory and invasive activities were assessed by wound healing and Matrigel invasion assays, respectively. Cell proliferation was determined by MTT assay. Slug expression was evaluated by Western blot, immunofluorescence, and immunohistochemistry. Restoration of miR-1 expression suppressed the migratory and invasive activities of chordoma cells. Transfection of miR-1 inhibited cell proliferation both time- and dose-dependently in chordoma. MiR-1 transfected cells showed inhibited Slug expression. Slug was over-expressed in chordoma cell lines and advanced chordoma tissues. In conclusion, we have shown that miR-1 directly targets the Slug gene in chordoma. Restoration of miR-1 suppressed not only proliferation, but also migratory and invasive activities, and reduced the Slug expression in chordoma cells. These results collectively indicate that miR-1/Slug pathway is a potential therapeutic target because of its crucial roles in chordoma cell growth and migration. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1075-1082, 2014. [ABSTRACT FROM AUTHOR]

ABSTRACT Reliable prognostic biomarkers for chordoma have not yet been established. Recent studies revealed that expression of miRNA-1 (miR-1) is frequently downregulated in several cancer types including chordoma. The goal of this follow-up study is to investigate the expression of miR-1 as a prognostic biomarker and further confirm the functional role of miR-1 in chordoma cell growth and proliferation. We determined the relative expression levels of miR-1 and Met in chordoma tissue samples and correlated those to clinical variables. The results showed that miR-1 was downregulated in 93.7% of chordoma tissues and expression was inversely correlated with Met expression. miR-1 expression levels also correlated with clinical prognosis. To characterize and confirm the functional role of miR-1 in the growth and proliferation of chordoma cells, miR-1 precursors were stably transfected into chordoma cell lines UCH-1 and CH-22. Cell Proliferation Assay and MTT were used to evaluate cell growth and proliferation. Restoring expression of miR-1 precursor decreased cell growth and proliferation in UCH-1 and CH-22 cells. These results indicate that suppressed miR-1 expression in chordoma may in part be a driver for tumor growth, and that miR-1 has potential to serve as prognostic biomarker and therapeutic target for chordoma patients. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:695-701, 2014. [ABSTRACT FROM AUTHOR]

While liposarcoma is the second most common soft tissue malignant tumor, the molecular pathogenesis in this malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade liposarcomas and benign lipomas across multiple disease sites, as well as two liposarcoma cell lines, using multiplexed mutational analysis. Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways. Liposarcoma cell lines were used to determine the effects of PI3K targeted drug treatment with or without chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human liposarcoma patients (22%). No PIK3CA mutations were identified in benign lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant liposarcoma samples. PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in liposarcoma cell lines and induced apoptosis. Importantly, combination with PI-103 treatment strongly synergized the growth-inhibitory effects of the chemotherapy drugs doxorubicin and cisplatin in liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important cancer mechanism in liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with chemotherapy could be exploited as a novel strategy in the treatment of liposarcoma. [ABSTRACT FROM AUTHOR]

Highlights: [•] CDK11 is highly expressed in liposarcoma tissues. [•] CDK11 expression is critical for liposarcoma cell growth and survival. [•] CDK11 knockdown enhances the cytotoxic effect of chemotherapeutic agent in liposarcoma cells. [•] CDK11 may be a promising therapeutic target for the treatment of liposarcoma. [Copyright &y& Elsevier]

The article offers information on malignant musculoskeletal tumors which is infrequent and has relatively aggressive clinical courses. It informs about chondrosarcoma which has no characteristic molecular alteration. It discusses bone morphogenetic protein pathway is active in central chondrosarcomas and the activity-correlated grade.

Background Development of a pre-vascularized tissue-engineered construct with intrinsic vascular system for cell growth and tissue formation still faces many difficulties due to the complexity of the vascular network of natural bone tissue. The present study was to design and form a new vascularized tissue-engineered construct using pre-differentiated rADSCs, arteriovenous vascular bundle and porous nHA-PA 66 scaffold. Methods rADSCs were pre-differentiated to endothelial cells (rADSCs-Endo) and then incorporated in nHA-PA 66 scaffolds in vitro. Subsequently, in vivo experiments were carried out according to the following groups: Group A (rADSCs-Endo/nHA-PA 66 scaffold with arteriovenous vascular bundle), Group B (rADSCs/nHA-PA 66 scaffold with arteriovenous vascular bundle); Group C (nHA-PA66 scaffold with arteriovenous vascular bundle), Group D (nHAPA 66 scaffold only). The vessel density and vessel diameter were measured based on histological and immunohistochemical evaluation, furthermore, the VEGF-C, FGF-2 and BMP-2 protein expressions were also evaluated by western blot analysis. Results The results of in vivo experiments showed that the vessel density and vessel diameter in group A were significantly higher than the other three groups. Between Group B and C, no statistical difference was observed at each time point. In accordance with the results, there were dramatically higher expressions of VEGF-C and FGF-2 protein in Group A than that of Group B, C and D at 2 or 4 weeks. Statistical differences were not observed in VEGF-C and FGF-2 expression between Group B and C. BMP-2 was not expressed in any group at each time point. Conclusions Compared with muscular wrapping method, arteriovenous vascular bundle implantation could promote vascularization of the scaffold; and the angiogenesis of the scaffold was significantly accelerated when pre-differentiated rADSCs (endothelial differentiation) were added. These positive results implicate the combination of pre-differentiated rADSCs (endothelial differentiation) and arteriovenous vascular bundle may achieve rapidly angiogenesis of biomaterial scaffold. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common primary malignant tumor of bone. Patients with localized osteosarcoma are routinely treated with chemotherapy and surgery. However, many of these patients eventually relapse after these treatments. In such cases, there are limited treatment options for these patients and most will eventually die with metastatic disease. Therefore, it is imperative to identify better therapeutic strategies. Hedgehog-GLI is responsible for the development of vertebrate embryonic and tumorigenesis. Specifically, the transcription factor, GLI-2, plays a key role in development of normal prostate. Aberrant activation of GLI-2 is correlated with various malignancies. We observe that GLI-2 is highly expressed in osteosarcoma cell lines, and this correlates with poor clinical outcomes in patients. Knockdown of GLI-2 by siRNA decreases osteosarcoma cell proliferation and viability, which eventually induces cell death as revealed in both in 2D and 3D cultures. In addition, we notice that administration of GLI-2 siRNA can increase the sensitivity of osteosarcoma cells to chemotherapeutic drugs. These findings suggest GLI-2 is required for osteosarcoma cell proliferation and survival. GLI-2 may be exploited as a therapeutic target for the treatment of osteosarcoma patients. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 502-509, 2013 [ABSTRACT FROM AUTHOR]

The article offers information on advances related to bone tumors. It discusses malignant tumors and benign tumors including ewing sarcoma, osteosarcoma and benign cartilaginous tumors. It reviews the efforts to find potential targets for systemic therapy for malignant tumors. It refers to the formation of a transcriptional complex with RNA helicase A (RHA) which is responsible for Ewing sarcoma. It discusses the various approached and clinical trials for combating osteosarcoma.

Chordoma is a rare primary malignant bone tumor and there exist only a few established human chordoma cell lines. The scarcity of robust chordoma cell lines has limited the ability to study this tumor. In this report, we describe the establishment of a novel chordoma cell line and characterize its in vitro and in vivo behaviors. The tumor tissue was isolated from a patient with recurrent chordoma of the sacrum. After 6 months in culture, the chordoma cell line, referred here as CH22, was established. Microscopic analysis of two-dimensional culture confirmed that the CH22 cells exhibited a typical vacuolated cytoplasm similar to the well-established chordoma cell line U-CH1. Electron microscopy showed cohesive cells with numerous surface filopodia, pockets of glycogen and aggregates of intermediate tonofilaments in cytoplasm. Three-dimensional culture revealed that the CH22 cells could grow and form clusters by day 8. The MTT assays demonstrated that, compared with sensitive osteosarcoma cell lines, CH22 cells were relatively resistant to conventional chemotherapeutic drugs. Western blotting and immunofluorescence analysis confirmed that the CH22 cells expressed brachyury, vimentin, and cytokeratin. Finally, histological analysis of CH22 xenograft tumor tissues demonstrated the appearance of physaliphorous cells and positive staining of brachyury, cytokeratin, and S100. By CT and MRI, imaging xenografts showed the typical appearances seen in human chordomas. These findings suggest that the established novel human chordoma cell line CH22 and its tumorigenecity in SCID nude mice may serve as an important model for studying chordoma cell biology and the development of new therapeutic modalities. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1666-1673, 2012 [ABSTRACT FROM AUTHOR]

Development of multidrug resistance (MDR) during chemotherapy is a fundamental obstacle associated with cancer care. Prior studies have identified (2-(4-methoxyphenyl)-4-quinolinyl)-(2-piperidinyl)-methanol (5) (NSC23925) to be a small molecule agent that reverses MDR in cancer cells. We synthesized all four isomers of 5 and analyzed them by liquid chromatography–mass spectrometry (LCMS). Structure–activity relationships for reversing MDR were evaluated. Isomer 11 demonstrated the most potent activity. 11 reversed MDR in several drug-resistant cell lines expressing Pgp, including ovarian, breast, colon, uterine, and sarcoma cancer. 11 resensitized these cell lines to paclitaxel, doxorubicin, mitoxantrone, vincristine, and trabectedin with no effect on cell sensitivity to cisplatin, topotecan, and methotrexate. 11 significantly enhanced in vivo antitumor activity of paclitaxel in MDR xenograft models, without increasing the level of paclitaxel toxicity. In conclusion, 11 and derivatives of this compound may hold therapeutic value in the treatment of MDR-dependent cancers. [ABSTRACT FROM AUTHOR]

The article discusses the clinicopathology in five case studies of patients with sarcoidosis of the spine. The cases include a 48-year-old man with numbness in his hand and neck pain, a 51-year-old woman with pulmonary sarcoidosis and thoracic back pain, and a 57-year-old man with lytic lesions in the thoracic spine. The article concludes surgery should only be performed when there is spinal cord compression or when there is instability secondary to a fracture.

The article discusses a review of 21 cases of cases of chondrosarcoma that involve the spine above the sacrum surgically treated between 1984-2006 in a single center, for the determination of the effect of modern surgical and aggressive radiation techniques on patients with spinal chondrosarcoma. The review showed the association of resection of the en bloc, absence of metastasis, low-grade tumors, and negative margins to an improvement in overall survival.

Osteosarcoma is the most common primary malignancy of bone. Patients with localized disease are routinely treated with surgery and chemotherapy. Unfortunately, many of these patients eventually relapse even after high-dose pre- and postoperative chemotherapy. Upon recurrence of the tumor locally or distantly, they have limited treatment options that are usually unsuccessful. Our prior studies screening lentiviral shRNA libraries, searching for kinases involved in osteosarcoma cell growth and proliferation have identified the Rho-associated coiled-coil containing protein kinase 1 (ROCK1) as a possible hit. We show in this study that ROCK1 is highly expressed in various tumor cell lines and tumor tissues from osteosarcoma patients. ROCK1 knockdown by synthetic siRNA decreases cell proliferation, viability and induces apoptosis in osteosarcoma cell lines KHOS and U-2OS. Finally, we established the relationship between expression levels of ROCK1 and clinical prognosis in osteosarcoma patients by using immunohistochemistry. There were significant differences in overall survival between cohorts of patients with ROCK1 levels categorized as high-staining, moderate-staining, and low-staining. High levels of ROCK1 were associated with poor outcomes in clinical osteosarcoma. These findings suggest that knockdown of ROCK1 inhibits proliferation and induces apoptosis in osteosarcoma cell lines. ROCK1 may be a promising therapeutic target for the treatment of osteosarcoma patients. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29: 1259-1266, 2011 [ABSTRACT FROM AUTHOR]

Purpose: To better understand the mechanisms of cytotoxicity and cell death induced by HDACI PCI-24781 in bone sarcoma cells. Methods: Four bone sarcoma cell lines were treated with PCI-24781, and the cytotoxicity was investigated. Further, accumulation of acetylated histones, p21, and PARP cleavage were evaluated in PCI-24781-treated cells. The synergistic effect of PCI-24781 to doxorubicin and its mechanism was investigated in bone sarcoma cells. Results: MTT assay demonstrated that the growth of bone sarcoma cells was inhibited after treatment with PCI-24781. Accumulation of acetylated histones, p21, and PARP cleavage were found in PCI-24781-treated cells. Expression of DNA repair protein RAD51 was inhibited, and the expression of apoptosis protein GADD45α was induced by PCI-24781 in bone sarcoma cells. Bone sarcoma cells treated with PCI-24781 become more sensitive to doxorubicin. The caspase-3/7 activity was increased with doxorubicin and PCI-24781 treatment in these cells. Conclusions: HDACI PCI-24781 has a synergistic effect on doxorubicin-induced apoptosis in bone sarcoma cells. [ABSTRACT FROM AUTHOR]

The article provides information on an experimental study conducted to investigate the activation of Src/Stat3 pathways in chordomas and blockage of this pathway as a possible strategy for chordoma treatment. It notes that the arrival of molecularly targeted therapies has raised interest for their use in the treatment of chordomas, despite limited understanding of molecular markers in chordomas. The study concluded that the blockage of Src/Stat3 signaling pathway by CDDO-Me is a possible strategy for chordoma treatment.

Abstract: Background context: Because of the low incidence, treatment recommendations for spinal osteosarcoma are guided by the results of small series and case reports. Many include patients who presented for treatment over the course of three to four decades. Purpose: The goal of this investigation was to report the treatments, results, and overall survivorship of 26 patients treated for osteosarcoma of the spine at a single institution. Study design: Retrospective prognostic series (Level III evidence). Patient sample: Twenty-six patients treated at a single center for osteosarcoma of the spine over a 26-year period. Outcome measures: Estimation of patient survival, local recurrence, and the presence of metastatic disease. Methods: We performed a retrospective review of cases of osteosarcoma involving the spine treated at our institution between 1982 and 2008. Medical charts, radiology reports, pathology reports, and operative notes were reviewed for all patients. Available imaging studies were also reviewed. The log-rank test was used to compare baseline differences between groups. Survivorship analysis was performed using Kaplan–Meier methodology. The effect of Paget osteosarcoma, type of resection, presence of local recurrence, tumor size, surgical margins, and metastases on overall survival were also investigated using the log-rank test. Results: Twenty-six patients were included for review in this study. Twenty individuals were treated surgically, and 24 were treated with radiation with a mean dose of 62.2 Gy (range 20–84.7 Gy). Twenty-five patients received chemotherapy. Of those treated surgically, seven received en bloc resection. The median overall survival for all patients in our series was 29.5 months (standard error 14.7, 95% confidence interval 0.6–58). Local recurrence developed in 7 patients (27%), and metastasis occurred in 16 individuals (62%). Patients with Paget osteosarcoma had worse overall survival (p<.001). Conclusions: Results presented here confirm a poor prognosis for patients with spinal osteosarcoma. Although combination therapies, including surgery, chemotherapy, and high-dose radiation, achieve adequate short-term survival, the 5-year mortality rate remains high. [Copyright &y& Elsevier]

Abstract: We describe an optimized systematic screen of known kinases using osteosarcoma cell lines (KHOS and U-2OS) and a lentiviral-based short hairpin RNA (shRNA) human kinase library. CellTiter 96®AQueous One Solution Cell Proliferation Assay was used to measure cell growth and survival. We identified several kinases, including human polo-like kinase (PLK1), which inhibit cell growth and induce apoptosis in osteosarcoma cells when knocked down. cDNA rescue and synthetic siRNA assays confirm that the observed phenotypic changes result from the loss of PLK1 gene expression. Furthermore, a small molecule inhibitor to PLK1 inhibited osteosarcoma cell growth and induced apoptosis. Western blot analysis confirmed that PLK1 is highly expressed and activated in several osteosarcoma cell lines as well as in resected tumor samples. Immunohistochemistry analysis showed that patients with high PLK1 tumor expression levels correlated with significantly shorter survival than patients with lower levels of tumor PLK1 expression. These results demonstrate the capability and feasibility of a high-throughput screen with a large collection of lentiviral kinases and its effectiveness in identifying potential drug targets. The development of more potent inhibitors that target PLK1 may open doors to a new range of anti-cancer strategies in osteosarcoma. [Copyright &y& Elsevier]

Stat3 expression in cancer may have important prognostic and therapeutic value, but there has been no reports correlating Stat3 expression with prognosis in patients with osteosarcoma. The goal of this study is to correlate patient prognosis with the expression of Stat3 in osteosarcoma tissue and determine the effectiveness of blocking this pathway in osteosarcoma cell lines by Stat3 inhibitor, CDDO-Me. We examine the expression levels of Stat3 and pStat3 in osteosarcoma cell lines and primary tissues by Western blot analysis. We also evaluate the levels of pStat3 expression in osteosarcoma tissue microarray (TMA) by immunohistochemistry. We use clinical data to determine the impact of levels of Stat3 expression on patient prognosis. Finally, we evaluated the effect of CDDO-Me on the inhibition of activated Stat3 pathway in osteosarcoma cell lines using MTT assay and Western blot analysis. Stat3 is observed to be activated in osteosarcoma tissues as well as in cultured cell lines. Overexpression of pStat3 is associated with poor prognosis. CDDO-Me inhibits the growth of osteosarcoma cell lines and induces apoptosis as well. Our results suggest that Stat3 may be a prognostic indicator and potential therapeutic target for osteosarcoma. Blocking the pathway of Stat3 may lead to develop new therapeutic strategies against osteosarcoma. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:971-978, 2010 [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the characterization of three chordoma cell lines. Though produced, their characterization is reportedly incomplete, rendering them useless for preclinical models. The cell lines were cultured from different tissues, producing CH 8, U-CH1, and GP 60. A comparison of the morphology and proliferation of chordoma cells cultured in plates with or without collagen substrate is also provided.

Emerging evidence suggests that microRNA (miRNA) expression signatures in cancer may have important diagnostic, prognostic, and therapeutic value, but there is no data on miRNA expression in chordoma. The purpose of this study was to identify the role of miRNAs in human chordoma. We analyzed miRNA expression in chordoma-derived cell lines and chordoma tissue by using miRNA microarray technology with unsupervised hierarchical clustering analysis. The relative expression levels of these miRNAs were confirmed by real-time quantitative RT-PCR and Northern blot analysis. To characterize the potential role of miRNA-1, miRNA-1 was stably transfected into a chordoma cell line, UCH1. The expression of miRNA-1 targeted gene Met in chordoma tissues was also studied. We observe that human chordoma tissues and cell lines can be distinguished from normal muscle tissue by comparing miRNA expression profiles. Several miRNAs were differentially expressed in chordoma cell lines compared to controls, and similar expression patterns were found in primary chordoma tissues. Importantly, we were able to show for the first time, to our knowledge, that expression of miRNA-1 and miRNA-206, two miRNAs implicated in a number of other cancer types, were markedly decreased in both chordoma tissues and cell lines. When chordoma cell lines were transfected with miRNA-1, downregulation of known miRNA-1 targets was observed. These targets included Met and HDAC4-two genes that were observed to be overexpressed in chordoma. Our results demonstrate that some miRNAs are differentially expressed in chordoma and, in particular, miRNA-1 may have a functional effect on chordoma tumor pathogenesis. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:746-752, 2010 [ABSTRACT FROM AUTHOR]

Background: The use of neo-adjuvant chemotherapy in treating osteosarcoma has improved patients' average 5 year survival rate from 20% to 70% in the past 30 years. However, for patients who progress after chemotherapy, its effectiveness diminishes due to the emergence of multi-drug resistance (MDR) after prolonged therapy. Methodology/Principal Findings: In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure resulting from MDR, we designed and evaluated a novel drug delivery system for MDR1 siRNA delivery. Novel biocompatible, lipid-modified dextran-based polymeric nanoparticles were used as the platform for MDR1 siRNA delivery; and the efficacy of combination therapy with this system was evaluated. In this study, multi-drug resistant osteosarcoma cell lines (KHOSR2 and U-2OSR2) were treated with the MDR1 siRNA nanocarriers and MDR1 protein (P-gp) expression, drug retention, and immunofluoresence were analyzed. Combination therapy of the MDR1 siRNA loaded nanocarriers with increasing concentrations of doxorubicin was also analyzed. We observed that MDR1 siRNA loaded dextran nanoparticles efficiently suppresses P-gp expression in the drug resistant osteosarcoma cell lines. The results also demonstrated that this approach may be capable of reversing drug resistance by increasing the amount of drug accumulation in MDR cell lines. Conclusions/Significance: Lipid-modified dextran-based polymeric nanoparticles are a promising platform for siRNA delivery. Nanocarriers loaded with MDR1 siRNA are a potential treatment strategy for reversing MDR in osteosarcoma. [ABSTRACT FROM AUTHOR]

The article presents a study that examines the seven cases of patients with monostotic fibrous dysplasia of the spine. It says that a literature review using the PubMed search engine was conducted to analyze the history, physical examination, histologic characteristics and clinical follow-up evaluations of the patients. It reveals that pain was the most common symptom for patients with monostotic fibrous dysplasia of the spine. Moreover, bisphosphonates were found to cure bone pain.

Osteosarcoma is the most common primary malignant bone tumor affecting children and adolescents. The majority of patients are treated by surgery and chemotherapy but have limited alternative therapeutic options. Kinases play an important role in the growth and survival of tumor cells. We aim to identify specific kinases to be vital in the survival of osteosarcoma cells and thus may be a key target in creating novel anticancer therapies. A lentiviral short hairpin RNA kinase library, screened osteosarcoma cells, identified kinase minibrain-related kinase (Mirk) (Dyrk1B) as a potential target. Knockdown Mirk expression could inhibit cell growth and induce apoptosis. Chemically synthetic small interfering RNA knockdown and complementary DNA rescue assay further confirmed the results from the decrease of Mirk gene expression. The relationship between Mirk gene expression and the clinical characteristics of patients with osteosarcoma was investigated using tissue microarray and immunohistochemistry analysis. The data indicate that the overall survival rate of patients with Mirk high staining (high levels of Mirk protein expression) is significantly shorter than those with Mirk low staining and moderate staining. This highlights Mirk’s potential to serve as a promising target for molecular therapy in the treatment of osteosarcoma. [ABSTRACT FROM PUBLISHER]

Background: The activation of signal transducer and activator of transcription 3 (Stat3) pathway correlates with tumor growth, survival, drug resistance and poor prognosis in osteosarcoma. To explore the potential therapeutic values of this pathway, we assessed both the expression and the activation of Stat3 pathway in several pairs of multidrug resistant (MDR) osteosarcoma cell lines, and tissues. To explore the potential therapeutic values of this pathway, we analyzed the ability of the synthetic oleanane triterpenoid, C-28 methyl ester of 2-cyano-3,12-dioxoolen-1,9-dien-28- oic acid (CDDO-Me), to inhibit Stat3 expression and activation as well as its effects on doxorubicin sensitivity in osteosarcoma cells. Methods: Expression of Stat3, phosphorylated Stat3 (pStat3) and Stat3 targeted proteins, including Bcl-XL, Survivin and MCL-1 were determined in drug sensitive and MDR osteosarcoma cell lines and tissues by Western blot analysis. The effect of CDDO-Me on osteosarcoma cell growth was evaluated by MTT and apoptosis by PARP cleavage assay and caspase-3/7 activity. Results: Stat3 pathway was activated in osteosarcoma tissues and in MDR cell lines. CDDO-Me inhibited growth and induced apoptosis in osteosarcoma cell lines. Treatment with CDDO-Me significantly decreased the level of nuclear translocation and phosphorylation of Stat3. The inhibition of Stat3 pathway correlated with the suppression of the antiapoptotic Stat3 targeted genes Bcl-XL, survivin, and MCL-1. Furthermore, CDDO-Me increased the cytotoxic effects of doxorubicin in the MDR osteosarcoma cell lines. Conclusions: Stat3 pathway is overexpressed in MDR osteosarcoma cells. CDDO-Me significantly inhibited Stat3 phosphorylation, Stat3 nuclear translocation and induced apoptosis in osteosarcoma. This study provides the framework for the clinical evaluation of CDDO-Me, either as monotherapy or perhaps even more effectively in combination with doxorubicin to treat osteosarcoma and overcome drug resistance. [ABSTRACT FROM AUTHOR]

Background: ET-743 (trabectedin, Yondelis®) and PM00104 (Zalypsis®) are marine derived compounds that have antitumor activity. ET-743 and PM00104 exposure over sustained periods of treatment will result in the development of drug resistance, but the mechanisms which lead to resistance are not yet understood. Methodology/Principal Findings: Human chondrosarcoma cell lines resistant to ET-743 (CS-1/ER) or PM00104 (CS-1/PR) were established in this study. The CS-1/ER and CS-1/PR exhibited cross resistance to cisplatin and methotrexate but not to doxorubicin. Human Affymetrix Gene Chip arrays were used to examine relative gene expression in these cell lines. We found that a large number of genes have altered expression levels in CS-1/ER and CS-1/PR when compared to the parental cell line. 595 CS-1/ER and 498 CS-1/PR genes were identified as overexpressing; 856 CS-1/ER and 874 CS-1/PR transcripts were identified as underexpressing. Three zinc finger protein (ZNF) genes were on the top 10 overexpressed genes list. These genes have not been previously associated with drug resistance in tumor cells. Differential expressions of ZNF93 and ZNF43 genes were confirmed in both CS-1/ER and CS-1/PR resistant cell lines by real-time RT-PCR. ZNF93 was overexpressed in two ET-743 resistant Ewing sarcoma cell lines as well as in a cisplatin resistant ovarian cancer cell line, but was not overexpressed in paclitaxel resistant cell lines. ZNF93 knockdown by siRNA in CS-1/ER and CS-1/PR caused increased sensitivity for ET-743, PM00104, and cisplatin. Furthermore, ZNF93 transfected CS-1 cells are relatively resistant to ET-743, PM00104 and cisplatin. Conclusions/Significance: This study suggests that zinc finger proteins, and ZNF93 in particular, are involved in resistance to ET-743 and PM00104. [ABSTRACT FROM AUTHOR]

To identify the apoptosis genes involved in the multidrug resistant phenotype of osteosarcoma. Multidrug resistant human osteosarcoma cell line (U-2 OS MR) and a drug sensitive parental cell line (U-2 OS) were both treated with paclitaxel and analyzed by the gene array containing 96 apoptosis associated genes. The different expression of the special apoptosis associated genes were further analyzed by Western blot in the multidrug resistant osteosarcoma cell lines (U-2 OS MR, KH OS R2) and the drug sensitive parental cell lines (U-2 OS, KH OS). One of the disregulated gene, RAIDD, was transfected into the multidrug resistant osteosarcoma cells for functional studies. RAIDD showed signs of significant expression in the U-2 OS cells after being treated with paclitaxel ( P < 0.01). However, the induction of RAIDD did not occur in U-2 OS MR cells ( P = 0.2). Subsequent analysis by Western blot confirmed the deficiency of the expression of RAIDD protein in U-2 OS MR. On the contrary, the expression of RAIDD could be significantly induced by paclitaxel and doxorubicin in U-2 OS cells as both time and dosage were deciding factors. It also demonstrated the cleavage of PARP associated with RAIDD expression in U-2 OS cells, but not however in U-2 OS MR cells after being treated with paclitaxel or doxorubicin. Similar results were found in osteosarcoma multidrug resistant cell line KH OS R2 and the drug sensitive parental cell line KH OS. Furthermore, over-expression of RAIDD in multidrug resistant cell lines could possibly reverse drug resistant phenotypes. This study indicate that impaired expression of RAIDD in drug induced apoptosis may play a role in the multidrug resistance of osteosarcoma cells. [ABSTRACT FROM AUTHOR]