curcumin and Rhabdomyosarcoma

The NF-κB-signaling pathway plays a crucial role in cancer progression, including muscle-derived cancers such as rhabdomyosarcoma or sarcoma. Several natural compounds have been studied for their ability to alter NF-κB signaling in these types of cancers. This review paper summarizes the current knowledge on the effects of natural compounds, including curcumin, resveratrol, quercetin, epigallocatechin-3-gallate, and berberine, on NF-κB signaling in muscle-derived cancers. These compounds have been shown to inhibit NF-κB signaling in rhabdomyosarcoma cells through various mechanisms, such as inhibiting the activation of the IKK complex and the NF-κB transcription factor. These findings suggest that natural compounds could be potential therapeutic agents for muscle-derived cancers. However, further research is needed to fully understand their mechanisms of action and potential clinical applications.

Topics: Curcumin; Humans; Muscles; NF-kappa B; Rhabdomyosarcoma; Signal Transduction

Approximately 7% of cancers arising in children and 1% of those arising in adults are soft tissue sarcomas (STS). Of these malignancies, rhabdomyosarcoma (RMS) is the most common. RMS survival rates using current therapeutic protocols have remained largely unchanged in the past decade. Thus, it is imperative that the main molecular drivers in RMS tumorigenesis are defined so that more precise, effective, and less toxic therapies can be designed. Curcumin, a common herbal supplement derived from plants of the

Topics: Adult; AMP-Activated Protein Kinases; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Child; Curcumin; Humans; Proto-Oncogene Proteins c-akt; Rhabdomyosarcoma; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, has an unfavorable outcome in advanced tumor stages with less than 30% failure‑free survival. Curcumin (CUR) is a promising drug in complementary oncology with few side effects but proven efficacy in various adult oncological entities. The present study analyzed the effects of CUR on pediatric (RMS) cell lines in vitro. RMS cell lines (RD and RH30), and skeletal muscle cells (SKMC) were treated with different doses of CUR (1.5‑30 µM) alone, with phototherapy (PDT, 488 nm) or in combination with vincristine (VCR) or dactinomycin (DAC). MTT assays were used for analysis of RMS tumor cell viability. Clonal cell growth was assessed via colony forming assays and migration of the cells was analyzed with scratch tests. Annexin V staining was used to determine apoptosis in flow cytometry. Possible RMS resistance towards CUR after long‑term treatment was analyzed with MTT assays. CUR decreased cell viability in all assessed RMS cell lines in a concentration‑dependent manner with IC50=14‑20 µM. CUR enhanced the effects of the cytotoxic drugs VCR or DAC, and led to reduced migration and increased cell apoptosis. In combination with PDT, CUR decreased the cell viability in minute quantities with up to a 10‑fold lower IC50 than without PDT. CUR effectively inhibited the malignant properties of pediatric RMS cells and should be focused on as a useful additional agent in standard chemotherapy of RMS in children.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Child; Combined Modality Therapy; Curcumin; Dactinomycin; Drug Synergism; Humans; Inhibitory Concentration 50; Phototherapy; Rhabdomyosarcoma; Signal Transduction; Vincristine

Synergistic effect of supercritical CO2 extracts of Curcuma species with conventional chemotherapeutic drugs was investigated in human alveolar (SJRH30) and embryonal (RD) rhabdomyosarcoma cell lines. The Curcuma amada (mango ginger) (CA) extract showed the highest levels of cytotoxicity with inhibitory concentration IC50 values of 7.133 µg/ml and 7.501 µg/ml for SJRH30 and RD cell lines, respectively, as compared with Curcuma longa (turmeric) and Curcuma xanthorrhiza (Javanese turmeric) extracts. CA showed synergistic cytotoxic effects with vinblastine (VBL) and cyclophosphamide (CP) as indicated by the combination index values of <1 for VBL + CA, CP + CA, and VBL + CP + CA combinations in both embryonal and alveolar rhabdomyosarcomas. When lower doses of CA (0.1-0.2 µg/ml) were combined with cancer drugs like CP and VBL, caspase-3 activity increased significantly compared with individual agents and correlated with the percentage of apoptotic cells. CA in combination with VBL and CP induced a higher percentage of apoptosis than single agents in both cell lines. CA also modulated the expression of genes associated with intrinsic pathway of apoptosis (Bcl-2, Bax, Bak, and p53) and also inhibited the expression of genes associated with inflammation such as COX-2 and NF-κB. Xenograft studies with SJRH30 tumors in nude mice showed that CA treatment inhibited tumor growth rate with and without VBL and increased the survival rate significantly. These results suggest that CA can be evaluated further as an adjuvant with cancer drugs for the treatment of rhabdomyosarcoma patients. Copyright © 2015 John Wiley & Sons, Ltd.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Caspase 3; Cell Line, Tumor; Curcuma; Cyclophosphamide; Drug Synergism; Humans; Inhibitory Concentration 50; Male; Mice; Mice, Nude; NF-kappa B; Plant Extracts; Rhabdomyosarcoma; Vinblastine; Xenograft Model Antitumor Assays

Rhabdomyosarcoma is a soft tissue sarcoma mainly seen in children. Despite considerable progress within the last few years, therapeutic approaches for this type of tumor are still limited. The respective tumor cells originate from myogenic precursor cells and are characterized by a blockade in their differentiation program. Interestingly, there is a direct inverse correlation between the differentiation status of a specific rhabdomyosarcoma cell and its metastatic potential. Thus, here, we tested whether the ubiquitous transcription factor NF-κB, which regulates myogenic differentiation and is also a promising therapeutic target in the treatment of other types of tumors, might be an interesting candidate for the development of novel rhabdomyosarcoma treatment strategies. For this purpose, we analyzed NF-κB activity (classical pathway) in myoblasts with different differentiation potential, specifically in three different rhabdomyosarcoma cell lines. In addition, we inhibited NF-κB activity in these cells and analyzed the effects on myogenic differentiation. We show that after the induction of differentiation, NF-κB activity declines rapidly in normal myoblasts, but only slightly in rhabdomyosarcoma cells. However, after treatment of the cells with two different small-molecule NF-κB-inhibiting compounds, the IKK inhibitor curcumin and the proteasome inhibitor lactacystin, we found that neither curcumin nor lactacystin promoted myogenic differentiation in either normal myoblasts or rhabdomyosarcoma cells. Taken together, our data suggest that treatment with curcumin or lactacystin might not be a suitable approach in the treatment of rhabdomyosarcoma.

Topics: Acetylcysteine; Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Line, Tumor; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Muscle Development; Myoblasts; NF-kappa B; Phosphorylation; Rhabdomyosarcoma; Signal Transduction

Signal transducers and activators of transcription 3 (STAT3) signaling is persistently activated in many types of cancer cells, and represents a valid target for anticancer drug design. However, few reports have described the constitutive activation of STAT3 in human sarcoma cells. In this study, we demonstrate that the STAT3 signaling pathway is constitutively activated in human rhabodomyosarcoma cells (RH28, RH30, and RD2). We also investigated the inhibitory effects of two newly developed small molecules, LLL12 and FLLL32, on the STAT3 signaling pathway in human rhabodomyosarcoma cells. Both LLL12 and FLLL32 downregulated STAT3 constitutively and interleukin-6 (IL-6) stimulated phosphorylated STAT3 (p-STAT3). The inhibition of STAT3 via LLL12 and FLLL32 was confirmed by the inhibition of STAT3 DNA binding activity. The downstream targets of STAT3, cyclin D1, Bcl-xL, and survivin were also downregulated by LLL12 and FLLL 32 at both messenger RNA and protein levels. The potency of LLL12 and FLLL32 to inhibit proliferation/viability in human rhabodomyosarcoma cells (RH28, RH30, and RD2) was higher than that of the 5 previously reported Janus kinase 2 (JAK2)/STAT3 inhibitors (LLL3, WP1066, Stattic, S3I-201, and AG490) and curcumin. Thus, in this study, we investigated the inhibitory effects of two STAT3 inhibitors, LLL12 and FLLL32, on the STAT3 signaling pathway in human rhabodomyosarcoma cells; we also demonstrated their higher potency in inhibiting proliferation on human rhabodomyosarcoma cells as compared to other five JAK2/STAT3 inhibitors and curcumin.

Topics: Anthraquinones; Cell Growth Processes; Cell Line, Tumor; Cell Survival; Curcumin; Humans; Phosphorylation; Rhabdomyosarcoma; Signal Transduction; STAT3 Transcription Factor; Sulfonamides

Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Recently, we have shown that curcumin inhibits phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), two downstream effector molecules of the mammalian target of rapamycin complex 1 (mTORC1) in numerous cancer cell lines. This study was designed to elucidate the underlying mechanism. We observed that curcumin inhibited mTORC1 signaling not by inhibition of the upstream kinases, such as insulin-like growth factor 1 receptor (IGF-IR) and phosphoinositide-dependent kinase 1 (PDK1). Further, we found that curcumin inhibited mTORC1 signaling independently of protein phosphatase 2A (PP2A) or AMP-activated protein kinase AMPK-tuberous sclerosis complex (TSC). This is evidenced by the findings that curcumin was able to inhibit phosphorylation of S6K1 and 4E-BP1 in the cells pretreated with PP2A inhibitor (okadaic acid) or AMPK inhibitor (compound C), or in the cells expressing dominant-negative (dn) PP2A, shRNA to PP2A-A subunit, or dn-AMPKalpha. Curcumin did not alter the TSC1/2 interaction. Knockout of TSC2 did not affect curcumin inhibition of mTOR signaling. Finally, we identified that curcumin was able to dissociate raptor from mTOR, leading to inhibition of mTORC1 activity. Therefore, our data indicate that curcumin may represent a new class of mTOR inhibitor.

Topics: Adaptor Proteins, Signal Transducing; AMP-Activated Protein Kinases; Antineoplastic Agents; Calcium-Binding Proteins; Cell Cycle Proteins; Curcumin; HT29 Cells; Humans; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Phosphoproteins; Phosphorylation; Protein Serine-Threonine Kinases; Proteins; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Receptor, IGF Type 1; Regulatory-Associated Protein of mTOR; Rhabdomyosarcoma; Ribosomal Protein S6 Kinases; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factors

Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Here we show that curcumin inhibited growth of rhabdomyosarcoma cells (Rh1 and Rh30) (IC50 = 2-5 microM) and arrested cells in G1 phase of the cell cycle. Curcumin also induced apoptosis and inhibited the basal or type I insulin-like growth factor-induced motility of the cells. At physiological concentrations (2.5 microM), curcumin rapidly inhibited phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream effector molecules, p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), in a panel of cell lines (Rh1, Rh30, DU145, MCF-7 and Hela). Curcumin also inhibited phosphorylation of Akt in the cells, but only at high concentrations (>40 microM). The data suggest that curcumin may execute its anticancer activity primarily by blocking mTOR-mediated signaling pathways in the tumor cells.

Topics: Adaptor Proteins, Signal Transducing; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Curcumin; G1 Phase; Humans; Insulin-Like Growth Factor I; Phosphoproteins; Phosphorylation; Phytotherapy; Protein Kinases; Resting Phase, Cell Cycle; Rhabdomyosarcoma; Ribosomal Protein S6 Kinases; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53