Testing of SNS-032 in a Panel of Human Neuroblastoma Cell Lines with Acquired Resistance to a Broad Range of Drugs

Abstract

Novel treatment options are needed for the successful therapy of patients with high-risk neuroblastoma. Here, we investigated the cyclin-dependent kinase (CDK) inhibitor SNS-032 in a panel of 109 neuroblastoma cell lines consisting of 19 parental cell lines and 90 sublines with acquired resistance to 14 different anticancer drugs. Seventy-three percent of the investigated neuroblastoma cell lines and all four investigated primary tumor samples displayed concentrations that reduce cell viability by 50% in the range of the therapeutic plasma levels reported for SNS-032 (<754 nM). Sixty-two percent of the cell lines and two of the primary samples displayed concentrations that reduce cell viability by 90% in this concentration range. SNS-032 also impaired the growth of the multidrug-resistant cisplatin-adapted UKF-NB-3 subline UKF-NB-3(r)CDDP(1000) in mice. ABCB1 expression (but not ABCG2 expression) conferred resistance to SNS-032. The antineuroblastoma effects of SNS-032 did not depend on functional p53. The antineuroblastoma mechanism of SNS-032 included CDK7 and CDK9 inhibition-mediated suppression of RNA synthesis and subsequent depletion of antiapoptotic proteins with a fast turnover rate including X-linked inhibitor of apoptosis (XIAP), myeloid cell leukemia sequence 1 (Mcl-1), baculoviral IAP repeat containing 2 (BIRC2; cIAP-1), and survivin. In conclusion, CDK7 and CDK9 represent promising drug targets and SNS-032 represents a potential treatment option for neuroblastoma including therapy-refractory cases.

CDK9 is a prognostic marker and therapeutic target in pancreatic cancer

“…Interestingly, we detected a slight reduction in the total level of RNA Pol II upon treatment with SNS-032 for 72 h. This has been observed before by other authors and is most likely due to prolonged inhibition of transcriptional elongation. 25,26 In summary, exacerbated CDK9 in pancreatic cancer can be successfully suppressed by the clinically available CDK inhibitor SNS-032. Figure 5(a)).…”

Pediatric Brain Tumor Cell Lines

“…Pediatric brain tumor cell lines have been historically difficult to generate compared to pediatric tumors such as high risk neuroblastomas, of which a well-characterized panel of over a hundred cell lines is available for researchers [Keshelava, 2000;Loschmann, 2013]. Only five pediatric brain tumor cell lines were published prior to 1990 [Friedman, 1985;Jacobsen et al, 1985;Takeshita, 1987;Friedman, 1988;Yamada 1989].…”

Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport

“…HZ51, LP117, LP123, YS71, and YS80 were characterized by varying activity profiles in a set of drug-resistant neuroblastoma cell lines consisting of the cisplatin-(UKF-NB-3 r CDDP 1000 ), doxorubicin-(UKF-NB-3 r DOX 20 ), and vincristine-resistant (UKF-NB-3 r VCR 10 ) sub-lines of UKF-NB-3 [21,24] and the cell line Be(2)-C, a multi-drug resistant neuroblastoma cell line that was established from a patient post-treatment (2μM) or verapamil (5μM). * P < 0.05 relative to untreated control.…”

“…LP117 also sensitized a range of further ABCB1-expressing cell lines to vincristine, including two other neuroblastoma cell lines with acquired resistance to vincristine (IMR-32 r VCR 10 , UKF-NB-2 r VCR 10 ), UKF-NB-3 sub-lines adapted to doxorubicin (UKF-NB-3 r DOX 20 ) or paclitaxel (UKF-NB-3 r PCL 10 ), and the intrinsically ABCB1-expressing neuroblastoma cell line UKF-NB-4 [20,22,24] but did not sensitize UKF-NB-3 r DOX 20 or UKF-NB-3 r VCR 10 cells to the non-ABCB1 substrate cisplatin. These data, together with the finding that LP117 stimulates ABCB1 ATPase activity, suggest that LP117 and other pirinixic derivatives interfere with ABCB1 function, possibly being substrates.…”