Sarantis Panagiotis, Bokas Alexandros, Papadimitropoulou Adriana, Koustas Evangelos, Theocharis Stamatios, Papakotoulas Pavlos, Schizas Dimitrios, Papalampros Alexandros, Felekouras Evangelos, Papavassiliou Athanasios G, Karamouzis Michalis V
Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
Department of Medical Oncology, 'Theageneio' Cancer Hospital, 54639 Thessaloniki, Greece.
Int J Mol Sci. 2021 Jun 30;22(13):7053. doi: 10.3390/ijms22137053.
Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis; hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds.
胰腺癌（PC）被认为是一种具有高度血栓形成倾向的肿瘤；因此，低分子量肝素（LMWH）如替扎肝素通常用于PC患者。基于治疗PC等高恶性和难治性癌症的联合治疗方法，我们假设替扎肝素可以增强传统化疗药物的疗效并诱导有效的抗肿瘤活性。将PANC-1和MIAPaCa-2单独培养或与替扎肝素、纳米白蛋白结合型紫杉醇和吉西他滨联合培养。在NOD/SCID小鼠中使用注射PANC-1的模型对这些化合物进行体内评估。在体外实验中，替扎肝素通过诱导凋亡增强纳米白蛋白结合型紫杉醇和吉西他滨对mtKRAS PC细胞系的抗肿瘤作用。三联组合通过诱导凋亡、降低增殖潜能和血管生成发挥作用；因此，导致体内观察到的肿瘤体积减小。与双药联合（吉西他滨加纳米白蛋白结合型紫杉醇）相比，三联方案使肿瘤缩小了24.3%。联合策略可为PC患者的治疗创造新的治疗方法，实现更好的临床结果和延长生存期。需要进一步的前瞻性随机研究，对高于150 UI/Kg的各种浓度替扎肝素进行研究，可能会为传统治疗化合物提供有价值的协同作用。
