Novel therapeutic strategy targeting STMN1 using chlorambucil-conjugated pyrrole-imidazole polyamide in small cell lung cancer.

Abstract

Small cell lung cancer (SCLC) is aggressive, with limited treatment progress for decades. Stathmin 1 (STMN1) is a cytoplasmic phosphorylated protein that is specific to cancerous tissues including SCLC and is associated with malignancy. Pyrrole-imidazole polyamide (PIP) compounds decrease gene expression by binding to specific DNA sites and disturbing RNA transcription. In this study, we synthesized a novel chlorambucil-conjugated PIP compound targeting both the STMN1 promoter and STMN1 DNA sequences (Chb-STMN1 PIP) to evaluate its therapeutic efficacy against SCLC. We examined the expression of STMN1 in surgically resected tissues and cell line database. Suppression of STMN1 by Chb-STMN1 PIP was analyzed using RT-PCR, WB, and CAGE-seq in vitro. The anti-tumor effects of Chb-STMN1 PIP were evaluated in vitro and in vivo. STMN1 mRNA expression was higher in cell lines with more STMN1 copy number alterations. In vitro studies showed that Chb-STMN1 PIP treatment resulted in significant STMN1 suppression and cell viability reduction compared to the control groups. Administration of Chb-STMN1 PIP to an SCLC xenograft mouse model also showed a tumor reduction effect and significantly suppressed angiogenesis, proliferation potency, and cell viability of SCLC. CAGE analysis indicated that the expression of STMN1 was suppressed in Chb-STMN1 PIP-treated cells compared to that in control cells. A novel compound, Chb-STMN1 PIP, induced significant anti-tumor effects and suppressed STMN1 expression in SCLC cell lines. Furthermore, SCLC xenograft mouse models showed tumor shrinkage and reduced malignant properties. Targeting STMN1 with our developed PIP compound appears to be a novel strategy and promising in SCLC.