Abstract:BackgroundNovel-targeted therapies are in rapid development for the treatment of acute lymphoblastic leukemia (ALL) to overcome resistance and decrease toxicity. Survivin, a member of the inhibitor of apoptosis gene family and chromosome passenger complex, is critical in a variety of human cancers, including ALL. A well-established suppressor of survivin has been the small molecule, YM155. Reports are identifying other mechanisms of action for YM155. Therefore, we sought to investigate the mode of action and r… Show more
“…It was also in phase II clinical trials for malignant conditions in young patients such as refractory CNS malignancies 17 . YM155 causes downregulation of survivin and the induction of DNA damage 18, 19 , and it was evaluated in various clinical trials for single and combination therapy in prostate cancer, lymphoma and melanoma 20, 21 .Figure 1YM155 and lapatinib show high degree of synergy in neuroblastoma regardless of the MYCN and TRKA status. ( A ) Overview of the drug library used in the concentration matrix-based combination screen.…”
Adverse side effects of cancer agents are of great concern in the context of childhood tumors where they can reduce the quality of life in young patients and cause life-long adverse effects. Synergistic drug combinations can lessen potential toxic side effects through lower dosing and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model.
“…It was also in phase II clinical trials for malignant conditions in young patients such as refractory CNS malignancies 17 . YM155 causes downregulation of survivin and the induction of DNA damage 18, 19 , and it was evaluated in various clinical trials for single and combination therapy in prostate cancer, lymphoma and melanoma 20, 21 .Figure 1YM155 and lapatinib show high degree of synergy in neuroblastoma regardless of the MYCN and TRKA status. ( A ) Overview of the drug library used in the concentration matrix-based combination screen.…”
Adverse side effects of cancer agents are of great concern in the context of childhood tumors where they can reduce the quality of life in young patients and cause life-long adverse effects. Synergistic drug combinations can lessen potential toxic side effects through lower dosing and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model.
“…YM155 is a small-molecule survivin suppressor that distinctly interacts with the survivin core promoter region of 269 base pairs, specifically inhibiting the expression of survivin (4,53). YM155 has effects on gene expression and phosphorylation (54). A certain study demonstrated that YM155 effectively inhibited the expression of survivin mRNA in SGC-7901 and MKN-28 cells in a dose-dependent manner (55).…”
Section: Recent Therapeutic Approachesmentioning
confidence: 99%
“…Chang et al (54) suggested that patients need to be pre-selected for YM155 sensitivity to guarantee beneficial outcomes. Their findings confirmed that YM155 is an ideal candidate drug for therapeutic regimens when administered to a certain subgroup of patients (54). Further study is required to identify the underlying mechanism of selective sensitivity to YM155 in cancer cells.…”
Survivin, also known as baculoviral inhibitor of apoptosis repeat-containing 5, is a novel member of the inhibitor of apoptosis protein family. Survivin is highly expressed in tumors and embryonic tissues and is associated with tumor cell differentiation, proliferation, invasion and metastasis; however, survivin is expressed at low levels in normal terminally differentiated adult tissues. Meanwhile, the expression level of survivin is also a negative prognostic factor for patients with cancer. These unique characteristics of survivin make it an exciting potential therapeutic target for cancer treatment. This review will discuss the biological characteristics of survivin and its potential use as a treatment target to reduce cancer cell proliferation.
“…YM155 (sepantronium bromide) was introduced as a transcriptional suppressor of survivin expression that displayed activity against a broad range of cancer types in preclinical models. 1, 3 However, further studies suggested that the YM155-induced inhibition of survivin expression may be a secondary effect downstream of YM155-induced DNA damage 1, 4, 5 or associated with Myeloid Cell Leukemia 1 (Mcl-1) depletion. 6 …”
Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug's mechanism of action.
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