多西他赛/卡巴他赛和脂肪酸结合蛋白 5 抑制剂协同抑制前列腺癌生长。
Docetaxel/cabazitaxel and fatty acid binding protein 5 inhibitors produce synergistic inhibition of prostate cancer growth.
机构信息
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York.
Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, New York.
出版信息
Prostate. 2020 Jan;80(1):88-98. doi: 10.1002/pros.23921. Epub 2019 Oct 29.
BACKGROUND
Prostate cancer (PCa) remains the second leading cause of cancer-related death among men. Taxanes, such as docetaxel and cabazitaxel are utilized in standard treatment regimens for chemotherapy naïve castration-resistant PCa. However, tumors often develop resistance to taxane chemotherapeutics, highlighting a need to identify additional therapeutic targets. Fatty acid-binding protein 5 (FABP5) is an intracellular lipid carrier whose expression is upregulated in metastatic PCa and increases cell growth, invasion, and tumor formation. Here, we assessed whether FABP5 inhibitors synergize with semi-synthetic taxanes to induce cytotoxicity in vitro and attenuate tumor growth in vivo.
METHODS
PC3, DU-145, and 22Rv1 PCa cells were incubated with FABP5 inhibitors Stony Brook fatty acid-binding protein inhibitor 102 (SBFI-102) or SBFI-103 in the presence or absence of docetaxel or cabazitaxel, and cytotoxicity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay. Cytotoxicity of SBFI-102 and SBFI-103 was also evaluated in noncancerous cells. For the in vivo studies, PC3 cells were subcutaneously implanted into BALB/c nude mice, which were subsequently treated with FABP5 inhibitors, docetaxel, or a combination of both.
RESULTS
SBFI-102 and SBFI-103 produced cytotoxicity in the PCa cells. Coincubation of the PCa cells with FABP5 inhibitors and docetaxel or cabazitaxel produced synergistic cytotoxic effects in vitro. Treatment of mice with FABP5 inhibitors reduced tumor growth and a combination of FABP5 inhibitors with a submaximal dose of docetaxel reduced tumor growth to a larger extent than treatment with each drug alone.
CONCLUSIONS
FABP5 inhibitors increase the cytotoxic and tumor-suppressive effects of taxanes in PCa cells. The ability of these drugs to synergize could permit more efficacious antitumor activity while allowing for dosages of docetaxel or cabazitaxel to be lowered, potentially decreasing taxane-resistance.
背景
前列腺癌（PCa）仍然是男性癌症相关死亡的第二大主要原因。紫杉烷类药物，如多西他赛和卡巴他赛，被用于化疗初治去势抵抗性 PCa 的标准治疗方案中。然而，肿瘤常常对紫杉烷类化疗药物产生耐药性，这凸显了需要确定其他治疗靶点的必要性。脂肪酸结合蛋白 5（FABP5）是一种细胞内脂质载体，其在转移性 PCa 中的表达上调，并增加细胞生长、侵袭和肿瘤形成。在这里，我们评估了 FABP5 抑制剂是否与半合成紫杉烷类药物协同作用，以在体外诱导细胞毒性，并在体内减轻肿瘤生长。
方法
将 PC3、DU-145 和 22Rv1 PCa 细胞与 FABP5 抑制剂 Stony Brook 脂肪酸结合蛋白抑制剂 102（SBFI-102）或 SBFI-103 孵育，无论是否存在多西他赛或卡巴他赛，都使用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐测定法评估细胞毒性。还评估了 SBFI-102 和 SBFI-103 在非癌细胞中的细胞毒性。对于体内研究，将 PC3 细胞皮下植入 BALB/c 裸鼠中，随后用 FABP5 抑制剂、多西他赛或两者的组合进行治疗。
结果
SBFI-102 和 SBFI-103 在 PCa 细胞中产生细胞毒性。PCa 细胞与 FABP5 抑制剂和多西他赛或卡巴他赛共同孵育产生协同细胞毒性作用。用 FABP5 抑制剂治疗小鼠可减少肿瘤生长，用 FABP5 抑制剂联合亚最大剂量多西他赛治疗可比单独使用每种药物更显著地减少肿瘤生长。
结论
FABP5 抑制剂增加了紫杉烷类药物在 PCa 细胞中的细胞毒性和肿瘤抑制作用。这些药物的协同作用能力可以提高抗肿瘤活性，同时降低多西他赛或卡巴他赛的剂量，可能降低紫杉烷类药物的耐药性。
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