sm-164 and Bone-Neoplasms

The most challenging issue for breast cancer (BC) patients is metastasis to other organs because current therapies do not prevent or eliminate metastatic BC. Here, we show that SM-164, a small molecule inhibitor, which degrades inhibitor of apoptosis proteins (IAPs), eliminated early-stage metastases and reduced progression of advanced BC metastasis from MDA-MB-231 BC cells in bones and lungs of nude mice. Mechanistically, SM-164-induced BC cell death is TNFα-dependent, with TNFα produced by IL-4-polarized macrophages triggering MDA-MB-231 cell apoptosis in combination with SM-164. SM-164 also inhibited expression of RANKL, which mediates interactions between metastatic BC and host microenvironment cells and induces osteoclast-mediated osteolysis. SM-164 did not kill adriamycin-resistant BC cells, while adriamycin inhibited SM-164-resistant BC cell growth, similar to parental cells. We conclude that SM-164 is a promising therapeutic agent for early stage bone and lung metastasis from triple-negative breast cancer that should be given prior to conventional chemotherapy.

Topics: Animals; Apoptosis; Bone Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Doxorubicin; Female; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Mice; Mice, Nude; RANK Ligand; Triazoles; Triple Negative Breast Neoplasms

The antitumor effects of SM‑164 and adriamycin (ADM) on human osteosarcoma U2‑OS cells, the underlying mechanism are yet to be investigated. In the present study, U2‑OS cells were divided into control, ADM, SM‑164, and ADM + SM‑164 groups. In addition, cells treated with both SM‑164 and ADM were further divided into three subgroups: SM‑164 + ADM, SM‑164 + ADM + vector and SM‑164 + ADM + X‑linked inhibitor of apoptosis protein (XIAP) silencing groups. XIAP expression was achieved via transfection with shRNA lentiviral vectors. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to detect the expression of caspases‑7, ‑9, and ‑3, poly ADP‑ribose polymerase (PARP), XIAP, cellular inhibitor of apoptosis protein‑1 (cIAP‑1) and survivin. Cell viability and apoptosis were evaluated using MTT and flow cytometry assays, respectively. Compared with the control group, cell viability decreased, while apoptosis was increased in the ADM and SM‑164‑treatment group. ADM and SM‑164 treatment promoted the expression of caspases‑7, ‑9 and ‑3, and PARP, but reduced the expression of XIAP, survivin and cIAP‑1. Compared with ADM + SM‑164 group, XIAP silencing with ADM + SM‑164 treatment further reduced cell viability, promoted apoptosis, increased caspase‑7, ‑9 and ‑3, and PARP expression; however the expression of survivin and cIAP‑1 were reduced. Combined ADM and SM‑164 treatment may be considered as potential therapeutic agent in the treatment of osteosarcoma, possibly via reductions XIAP expression.

Topics: Antibiotics, Antineoplastic; Apoptosis; Bone Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Caspase 3; Cell Line, Tumor; Cell Survival; Down-Regulation; Doxorubicin; Drug Synergism; Humans; Inhibitor of Apoptosis Proteins; Osteosarcoma; Poly(ADP-ribose) Polymerases; RNA Interference; RNA, Small Interfering; Survivin; Triazoles; X-Linked Inhibitor of Apoptosis Protein

Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Baculoviral IAP Repeat-Containing 3 Protein; Bone Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Survival; Cyclohexanes; Dose-Response Relationship, Drug; Genetic Predisposition to Disease; HEK293 Cells; Humans; Inhibitor of Apoptosis Proteins; Mice, Knockout; Osteosarcoma; Phenotype; Pyrroles; Receptor-Interacting Protein Serine-Threonine Kinases; Retinoblastoma Protein; Signal Transduction; Thiazoles; TNF-Related Apoptosis-Inducing Ligand; Transfection; Triazoles; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases