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Simple Summary: Pancreatic cancer is presently the fourth most common cause of cancer-related death. Treatment options and prognosis are poor. Therefore, new therapeutic approaches are urgently needed. Molecular targeting of the interleukin-6/glycoprotein-130/signal transducer and activator of transcription 3 signaling cascade is a promising approach in pancreatic cancer therapy. The present study investigates the combined effect of the first-line chemotherapeutic paclitaxel with the small-molecule gp130 inhibitor SC144 and the non-steroidal selective estrogen receptor modulator raloxifene that both interfere with interleukin-6/glycoprotein-130 signaling. Experiments performed on a mouse model of pancreatic cancer and cell lines proved both molecules to enhance low-dose paclitaxel effects by increasing apoptosis in tumor cells or reducing interleukin-6 levels, respectively. These findings might be promising to improve treatment efforts in pancreatic cancer, while the paclitaxel side-effect profile could be improved by lowering paclitaxel doses. Interleukine-6 plays a key role in the progression and poor survival in pancreatic ductal adenocarcinoma (PDAC). The present study aimed to clarify if targeting the interleukin-6/glycoprotein-130 signaling cascade using the small-molecule gp130 inhibitor SC144 or raloxifene, a non-steroidal selective estrogen receptor modulator, enhances paclitaxel efficacy. MTT/BrdU assays or TUNEL staining were performed to investigate cell viability, proliferation and apoptosis induction in L3.6pl and AsPC-1 human pancreatic cell lines. In vivo, effects were studied in an orthotopic PDAC mouse model. Tumor specimens were analyzed by qPCR, immunohistochemistry and ELISA. Combination of paclitaxel/raloxifene, but not paclitaxel/SC144, enhanced proliferation and viability inhibition and increased apoptosis compared to single treatment in vitro. Synergy score calculations confirmed an additive influence of raloxifene on paclitaxel. In the PDAC mouse model, both combinations of raloxifene/paclitaxel and SC144/paclitaxel reduced tumor weight and volume compared to single-agent therapy or control. Raloxifene/paclitaxel treatment decreased survivin mRNA expression and showed tendencies of increased caspase-3 staining in primary tumors. SC144/paclitaxel reduced interleukin-6 levels in mice's tumors and plasma. In conclusion, raloxifene or SC144 can enhance the anti-tumorigenic effects of paclitaxel, suggesting that paclitaxel doses might also be reduced in combined chemotherapy to lessen paclitaxel side effects. [ABSTRACT FROM AUTHOR]