Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Chiba 299-0111, Japan.
Int J Oncol. 2013 Aug;43(2):431-8. doi: 10.3892/ijo.2013.1978. Epub 2013 Jun 7.
Fatty acid synthase is highly expressed in many types of human cancers. Cerulenin, a natural inhibitor of fatty acid synthase, induced apoptosis in the human colon cancer cell lines HCT116 and RKO. Oxaliplatin also induced cell death in these cell lines. Cerulenin treatment was associated with reduced levels of phosphorylated Akt, activation of p38 and induced caspase-3 cleavage and finally caused apoptosis. Oxaliplatin induced activation of the p53-p21 pathway and p38. In combination with cerulenin and oxaliplatin, activation of the p53-p21 pathway and p38 occurred in a smaller concentration and finally induced caspase-3 cleavage in a smaller concentration of cerulenin and oxaliplatin. In xenotransplanted SCID mice, the cerulenin + oxaliplatin group significantly inhibited tumor progression compared to the control, cerulenin and oxaliplatin groups. Based on these studies, inhibiting fatty acid synthase would be an effective strategy to treat unresectable colorectal cancer tumors in combination with oxaliplatin. Fatty acid synthase inhibitor would be one of the best counterparts of oxaliplatin, which reduces the dose and side-effects of oxaliplatin and would make it possible to endure the chemotherapy over a longer period.
脂肪酸合酶在许多类型的人类癌症中高度表达。 泽仑诺林，一种脂肪酸合酶的天然抑制剂，诱导人结肠癌细胞系 HCT116 和 RKO 凋亡。奥沙利铂也诱导这些细胞系的细胞死亡。泽仑诺林治疗与磷酸化 Akt 水平降低、p38 的激活以及诱导 caspase-3 切割有关，最终导致细胞凋亡。奥沙利铂诱导 p53-p21 途径和 p38 的激活。与泽仑诺林和奥沙利铂联合使用时，p53-p21 途径和 p38 的激活发生在更低的浓度，最终在更低浓度的泽仑诺林和奥沙利铂诱导 caspase-3 切割。在异种移植的 SCID 小鼠中，泽仑诺林+奥沙利铂组与对照组、泽仑诺林和奥沙利铂组相比，显著抑制肿瘤进展。基于这些研究，抑制脂肪酸合酶将是联合奥沙利铂治疗不可切除的结直肠癌肿瘤的有效策略。脂肪酸合酶抑制剂将成为奥沙利铂的最佳伴侣之一，它可以降低奥沙利铂的剂量和副作用，并使更长时间的化疗成为可能。
