Treatment of metastatic castration-resistant prostate cancer (mCRPC) remains clinically challenging due to tumor heterogeneity and drug resistance. Microtubule-targeting agents are a mainstay of mCRPC therapy, but limitations persist regarding progression-free survival. Pterocarpans have emerged as promising anti-cancer agents, exerting effects through inhibition of bipolar spindle formation, cell cycle arrest in mitosis, and apoptosis induction. In this study, we evaluated the cytotoxic and proteomic effects of the natural product (+)-PTC in PC-3 cells and compared its activity to nocodazole (microtubule depolymerizer) and monastrol (Eg5 inhibitor). Flow cytometry after 24 hours of treatment with 8.0 µM (+)-PTC or 0.25 µM nocodazole revealed a ~50% reduction in cell proliferation relative to controls. Proteomic analyses (LC-MS/MS, GSEA, PANTHER) showed that (+)-PTC shares over 80% of differentially expressed proteins with nocodazole, with 82% overlap among up-regulated and 84% among down-regulated proteins. Top up-regulated proteins (TTLL3, ANAPC7, PIK3CA, ARID4B, COL16A1) are involved in microtubule dynamics and cell cycling; top down-regulated ones (KDM2B, PTOV1, YWHAQ, PSMB6, DPP6) impact cell survival and checkpoints. Differential expression analyses identified key regulators of mitosis and stress response. These findings nominate (+)-PTC as a candidate for future mCRPC therapy.