Neuroblastoma Cell Death is Induced by Inorganic Arsenic Trioxide (As2O3) and Inhibited by a Normal Human Bone Marrow Cell-Derived Factor

Abstract

Three phenotypically distinct cell types are present in human neuroblastomas (NB) and NB cell lines: I-type stem cells, N-type neuroblastic precursors, and S-type Schwannian/melanoblastic precursors. The stimulation of human N-type neuroblastoma cell proliferation by normal human bone marrow monocytic cell conditioned medium (BMCM) has been demonstrated in vitro, a finding consistent with the high frequency of bone marrow (BM) metastases in patients with advanced NB. Inorganic arsenic trioxide (As2O3), already clinically approved for the treatment of several hematological malignancies, is currently under investigation for NB. Recent studies show that As2O3 induces apoptosis in NB cells. We examined the impact of BMCM on growth and survival of As2O3-treated NB cell lines, to evaluate the response of cultured NB cell variants to regulatory agents. We studied the effect of BMCM on survival and clonogenic growth of eleven As2O3-treated NB cell lines grown in sparsely seeded, non-adherent, semi-solid cultures. As2O3 had a strong inhibitory effect on survival of all tested NB cell lines. BMCM augmented cell growth and survival and reversed the inhibitory action of As2O3 in all tested cell lines, but most strongly in N-type cells. While As2O3 effectively reduced survival of all tested NB cell lines, BMCM effectively impacted its inhibitory action. Better understanding of micro-environmental regulators affecting human NB tumor cell growth and survival may be seminal to the development of therapeutic strategies and clinically effective agents for this condition.