Evaluation of siramesine, β-Lapachone, and palbociclib as novel maintenance therapies after chemotherapy in small cell lung cancer

Small cell lung cancer (SCLC) represents approximately 15 % of all lung cancer cases and is characterized by rapid proliferation and a high metastatic potential. In the search for new treatments, drug repurposing has gained increasing attention, particularly with FDA-approved agents such as palbociclib (PB). Other compounds with reported antitumor activity, including siramesine (SR) and β-Lapachone (LP), are also under investigation, although they remain unapproved for clinical use. In this study, we evaluated the antitumor activity and underlying mechanisms of SR, LP, and PB in the H69 cell line. Antiproliferative effects, apoptosis (via PARP1 and Bcl-2), autophagy (via LC3β and p62), and senescence (via p21) were analyzed. Antitumor activity was further investigated using the chick chorioallantoic membrane (CAM) assay in ovo. Additionally, in vivo therapeutic efficacy was evaluated in subcutaneous murine models bearing H69 tumors, both as monotherapy and as maintenance treatment. All three compounds reduced cell proliferation and colony formation. PB increased reactive oxygen species (ROS) levels and induced cellular senescence. In the CAM assay, tumors appeared less dense and showed reduced expression of the proliferation marker Ki-67. Interestingly, SR, LP, and PB significantly reduced tumor volume when administered as monotherapies in murine models of SCLC. Furthermore, when they were used as maintenance therapy following chemotherapy, these drugs enhanced the antitumor response. Therefore, our findings highlight SR, LP, and PB as promising therapeutic candidates for the treatment of SCLC.