Oral RKS262 reduces tumor burden in a neuroblastoma xenograft animal model and mediates cytotoxicity through SAPK/JNK and ROS activation in vitro

Rakesh K. Singh, Lee Dorf, Angelica DeMartino, Sharon Illenye, Karen Koto, Erika A. Currier, Takamaru Ashikaga, Kyu Kwang Kim, Laurent Brard, Giselle L. Saulnier Sholler

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8 Scopus citations

Abstract

Patients diagnosed with high-risk neuroblastoma (NB), an extracranial solid tumor in children, have metastases and low survival (30%) despite aggressive multi-modal therapy. Therefore new therapies are urgently needed. We show significant in vitro and in vivo antitumor efficacy of RKS262 in NB. RKS262 showed superior cytotoxicity (IC50 = 6-25 μM) against six representative NB cell lines compared to its parent analog nifurtimox (currently in phase 2). Pre-formulated RKS262 (150 mg/kg/daily) pellets administered orally, suppressed tumor growth (60%, p = 0.021) in NB xenograft mice within 28 days. RKS262-treated SMSKCNR cells showed TUNEL-positive DNA nicks and activation of ROS, MAP Ks (SAPK/JNK), caspase-3 and p53, along with suppression of the IGF-1R/PI3K/PKC pathway and the Bcl2 family of proteins. RKS262 caused G2/M-phase arrest and suppressed cdc-2, cyclin B1, p21 and cyclin D1/D4 expression. N-acetyl-cysteine (NAC; 10 mM) pre-treatment rescued cell viability of RKS262 (23 μM)-treated SMSKCNR cells and pre-treatment with ascorbic acid (100 μM) and a MAP K inhibitor SB203580 (20 μM) reversed SAP K/JNK, caspase-3 activation, PA RP-1 cleavage and suppression of IGF-1R, PI3K and PKC phosphorylation. Further, treatment with exogenous BDNF (50 nM) did not suppress SAP K/JNK or ROS activation due to RKS262. Rather, BDNF (50 nM), EGF (100 nM) and IGF-1 (100 nM) co-treatment with RKS262 induced a remarkable S-phase arrest rather than a G2/M phase arrest when RKS262 was used alone. In summary, RKS262 shows oral efficacy in NB xenograft animals and induces apoptosis in vitro in SMSKCNR cells via cell cycle arrest, MAP K and ROS activation, and suppression of IGF-1R/PI3K/PKC and Bcl2 family proteins in a growth factor (BDNF/EGF/IGF-1)-independent fashion.

Original languageEnglish (US)
Pages (from-to)1036-1045
Number of pages10
JournalCancer Biology and Therapy
Volume11
Issue number12
DOIs
StatePublished - Jun 15 2011

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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