Co-Administration of Fendiline Hydrochloride Enhances Chemotherapeutic Efficacy of Cisplatin in Neuroblastoma Treatment

Abstract

Despite significant improvement of neuroblastoma (NB) patients’ survival due to recent treatment advancements in recent years, NB is still associated with high mortality rate. In search of novel strategies to increase NB’s susceptibility to pharmacological treatments, we investigated the in vitro and in vivo effects of fendiline hydrochloride as an enhancer of cisplatin antitumor activity. To assess the modulation of fendiline treatment on cisplatin responses, we used in vitro (evaluating NB cell proliferation by XCELLigence technology and colony formation, and gene expression by RT-PCR) and in vivo (NB cell grafts in NOD-SCID mice) models of NB. NB cell treatment with fendiline induced the expression of the ncRNA NDM29, leading to cell differentiation and to the reduction of the expression of MDRs/ABC transporters linked to multidrug resistance. These events were correlated to higher NB cell susceptibility to cisplatin and, consequently, increased its cytotoxic potency. In vivo, this drug interaction causes an enhanced ability of cisplatin to induce apoptosis in NB masses, resulting in tumor growth reduction and prolonged animal survival rate. Thus, the administration of fendiline might be a possible novel therapeutic approach to increase cisplatin efficacy in aggressive and poorly responsive NB cases.

Efficacy of a Three Drug-Based Therapy for Neuroblastoma in Mice

“…Figure 1 reports the growth rate of tumor nodules and mice survival in the different experimental groups. Single treatments with acetazolamide or fendiline per se do not reduce tumor nodule growth, as shown by the daily recordings of nodule volume, which did not differ from DMSO-treated controls; cisplatin alone, at the dose used, had a moderate effect, but, in line with our previous results [7], the combined cisplatin/fendiline treatment reduced tumor growth much more effectively than low-dose cisplatin-based chemotherapy; conversely, no enhancing effects were observed in the co-treatment with cisplatin and acetazolamide, which induced an antitumor effect comparable to cisplatin alone. Interestingly, in the mice treated with the combination therapy which included all three molecules (Cis/Fen/Az), there was a reduced nodule growth rate equal to approximately one tenth of that observed in the vehicle-treated control mice, and if compared with the Cis/Fen treatment, the growth rate halved (Figure 1A,B).…”

“…It was also reported that fendiline, an L-type calcium blocker, causes cell death and reduction of proliferation and sensitization to cytotoxic drug activity of different tumor cell lines, through different mechanisms [40][41][42][43]. Among those, we recently identified a ncRNA named NDM29 whose stable overexpression is sufficient to induce neuronal differentiation of SKNBE2 NB cells preventing their tumorigenicity in vivo [6,7,9]. NDM29 acts mainly by downregulating the activity of ABC transporters thus increasing the susceptibility of NB cells to the effects of cisplatin.…”

“…In this scenario new, more effective therapies for NB treatment are urgently needed. Repurposing drugs already used for other pathologies as anticancer agents is a suitable approach to developing new therapeutic strategies in a relatively short time, as molecular targeted drugs already approved for pediatric use could be repurposed thus avoiding phase 1 trials [4][5][6][7][8].…”

“…Recently, we proposed a possible alternative pharmacological treatment for HR-NB based on the co-administration of the cytotoxic drug cisplatin and the antianginal agent fendiline hydrochloride, whose synergism increases the effectiveness of anticancer treatment, slowing down tumor growth in a NOD-SCID mouse model of the disease [7]. We found that the beneficial effect of fendiline co-administration is due to its ability to induce the expression of NDM29, an RNA polymerase (pol) III-transcribed non-coding (nc) RNA whose expression induces NB cells to differentiate into a nonmalignant neuron-like phenotype [9].…”

“…Using an in vivo xenograft model, we previously demonstrated that the combined treatment of cisplatin and fendiline reduces NB nodule growth more efficiently than cisplatin alone, thus increasing the overall survival of treated mice [7].…”