Cytotoxic Synergism between a Proprietary Commiphora mukul Gum Extract GU-MCT810, 2-deoxy-D-glucose, and Metformin in Human Alveolar Rhabdomyosarcoma and Hepatoma Cell Lines In vitro

In this investigation we have analyzed the synergism for the cytotoxic effect of a proprietary guggul gum extract (GU), 2-deoxy-D-glucose (2-DG) and metformin (Met) in SJRH30 human alveolar rhabdomyosarcoma and HepG2 hepatoma cell lines in vitro. 2-DG and Met as single agents have weak cytotoxic effects in both cell lines. However, the combination of GU+2-DG, GU+Met and 2-DG+Met showed synergism for cytotoxic effect by CompuSyn analysis. Therefore, GU can be included in the combination of drugs involving 2-DG and Met to have synergistic effect. GU also showed a dose-dependent increase in cellular glucose uptake in HepG2 cells like the antidiabetic drug 2,4-thiozolidine dione (TZ). The demonstration of synergism of anticancer effects between GU, metformin and 2-DG, suggest that their mechanisms are in general complementary, though further studies are required to delineate the mechanism of GU, 2-DG and metformin combinations.

Encouraging Early Outcomes of Treatment With Arsenic Trioxide Combined With Chemotherapy for Alveolar Rhabdomyosarcoma in Children: 4 Case Reports

BackgroundAlveolar rhabdomyosarcoma (ARMS) is a subtype of rhabdomyosarcoma characterized by its aggressive behavior and poor prognosis, highlighting the need for novel treatment options. Arsenic trioxide (ATO) has been shown to specifically inhibit tumor growth and the metastasis of ARMS in vitro by acting on the hedgehog pathway. Here we report on a pilot clinical study to evaluate the activity of an ATO-combined chemotherapy approach for the treatment of ARMS patients.MethodsWe designed a therapeutic schedule of an ATO-combined chemotherapy, incorporating comprehensive management according to the Intergroup Rhabdomyosarcoma Study Group protocol. ATO was administered at 0.16 mg/kg per day over 8 h via an IV for 10 days combined with a chemotherapeutic regimen of vincristine, actinomycin, and cyclophosphamide (VAC regimen) on the third day, which was repeated every 21 days. A total of eight cycles of ATO-combined chemotherapy were applied throughout the entire scheme.ResultsA total of three refractory/recurrent and one untreated ARMS patient, three male and one female, with a median age of 5.8 years (range, 5.1 to 12.5 years), were enrolled in the present study. All patients were sensitive to combined chemotherapy with ATO and achieved partial or complete remission during treatment. Except for reversible gastrointestinal reaction and myelosuppression, no other adverse events were observed during the process of treatment.ConclusionsThe combined chemotherapy of ATO and the VAC regimen exhibited beneficial activities against ARMS in pediatrics and was well tolerated, but prospective large-scale clinical trials are warranted to determine the long-term efficacy, optimal courses, and late toxicity in this population.

Reduced B7-H3 expression by PAX3-FOXO1 knockdown inhibits cellular motility and promotes myogenic differentiation in alveolar rhabdomyosarcoma

B7-H3 (also known as CD276) is associated with aggressive characteristics in various cancers. Meanwhile, in alveolar rhabdomyosarcoma (ARMS), PAX3-FOXO1 fusion protein is associated with increased aggressiveness and poor prognosis. In the present study, we explored the relationship between PAX3-FOXO1 and B7-H3 and the biological roles of B7-H3 in ARMS. Quantitative real time PCR and flow cytometry revealed that PAX3-FOXO1 knockdown downregulated B7-H3 expression in all the selected cell lines (Rh-30, Rh-41, and Rh-28), suggesting that PAX3-FOXO1 positively regulates B7-H3 expression. Gene expression analysis revealed that various genes and pathways involved in chemotaxis, INF-γ production, and myogenic differentiation were commonly affected by the knockdown of PAX3-FOXO1 and B7-H3. Wound healing and transwell migration assays revealed that both PAX3-FOXO1 and B7-H3 were associated with cell migration. Furthermore, knockdown of PAX3-FOXO1 or B7-H3 induced myogenin expression in all cell lines, although myosin heavy chain induction varied depending on the cellular context. Our results indicate that PAX3-FOXO1 regulates B7-H3 expression and that PAX3-FOXO1 and B7-H3 are commonly associated with multiple pathways related to an aggressive phenotype in ARMS, such as cell migration and myogenic differentiation block.