Department of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, 350122, China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
Cell Commun Signal. 2019 Sep 1;17(1):110. doi: 10.1186/s12964-019-0408-5.
Overexpression of ATP-binding cassette (ABC) transporters, such as ABCB1 and ABCG2, has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. A promising approach to reverse MDR is the combined use of nontoxic and potent ABC transporters inhibitor with conventional anticancer drugs. We previously reported that FW-04-806 (conglobatin) as a novel Hsp90 inhibitor with low toxicity, capable of attenuating Hsp90/Cdc37 /clients interactions and producing antitumor action in vitro and in vivo. Our early activity screening found that FW-04-806 at non-cytotoxic concentration was able to enhance the cytotoxicity of chemotherapeutic agents on the ABCB1 overexpressing cells. Therefore, we speculated that FW-04-806 might be a promising MDR reversal agent. In the present study we further investigated its reversal effect of MDR induced by ABC transporters in vitro and in vivo.
MTT assay in vitro and xenograftes in vivo were used to investigate reversal effect of FW-04-806 on MDR in ABCB1 or ABCG2 overexpressing cancer cells. To understand the mechanisms for the MDR reversal, we examined the effects of FW-04-806 on intracellular accumulation of doxorubicin (DOX, adriamycin, adr)/Rhodamine 123 (Rho 123), efflux of doxorubicin, expression levels of gene and protein of ABCB1 or ABCG2 and ATPase activity of ABCB1, and carried out molecular docking between FW-04-806 and human ABCB1.
The results indicated that FW-04-806 significantly enhanced the cytotoxicity of substrate chemotherapeutic agents on the ABCB1 or ABCG2 overexpressing cells in vitro and in vivo suggesting its reversal MDR effects. FW-04-806 increased the intracellular accumulation of DOX or Rho123 by inhibiting the efflux function of ABC transporters in MDR cells rather than in their parental sensitive cells. However, unlike other ABC transporter inhibitors, FW-04-806 had no effect on the ATPase activity nor on the expression of ABCB1 or ABCG2 on either mRNA or protein level. Molecular docking suggested that FW-04-806 may have lower affinity to the ATPase site, which was consistent with its no significant effect on the ATPase activity of ABCB1; However FW-04-806 may bind to substrate binding site in TMDs more stably than substrate anticancer drugs therefore obstruct the anticancer drugs pumped out of the cell.
FW-04-806 is a compound that has both anti-tumor and reversal MDR effects, and its antitumor clinical application is worth further study.
ATP 结合盒（ABC）转运蛋白的过度表达，如 ABCB1 和 ABCG2，已被证明是某些类型癌症多药耐药（MDR）的主要触发因素。逆转 MDR 的一种有前途的方法是将非毒性和有效的 ABC 转运蛋白抑制剂与传统抗癌药物联合使用。我们之前报道过，FW-04-806（conglobatin）作为一种新型 HSP90 抑制剂，具有低毒性，能够减弱 HSP90/Cdc37/客户相互作用，并在体外和体内产生抗肿瘤作用。我们的早期活性筛选发现，FW-04-806 在非细胞毒性浓度下能够增强 ABCB1 过表达细胞对化疗药物的细胞毒性。因此，我们推测 FW-04-806 可能是一种有前途的 MDR 逆转剂。在本研究中，我们进一步研究了它在体外和体内对 ABC 转运蛋白诱导的 MDR 的逆转作用。
体外 MTT 测定和体内异种移植用于研究 FW-04-806 对 ABCB1 或 ABCG2 过表达癌细胞 MDR 的逆转作用。为了了解 MDR 逆转的机制，我们研究了 FW-04-806 对阿霉素（DOX，多柔比星，adr）/罗丹明 123（Rho 123）的细胞内积累、DOX 外排、ABCB1 或 ABCG2 的基因和蛋白表达水平以及 ABCB1 的 ATP 酶活性的影响，并进行了 FW-04-806 与人类 ABCB1 之间的分子对接。
结果表明，FW-04-806 显著增强了 ABCB1 或 ABCG2 过表达细胞在体外和体内对底物化疗药物的细胞毒性，提示其具有逆转 MDR 作用。FW-04-806 通过抑制 MDR 细胞而非其亲本敏感细胞的外排功能，增加了 DOX 或 Rho123 的细胞内积累。然而，与其他 ABC 转运蛋白抑制剂不同，FW-04-806 对 ABCB1 的 ATP 酶活性或 ABCB1 或 ABCG2 的 mRNA 或蛋白水平的表达均没有影响。分子对接表明，FW-04-806 与 ATP 酶结合位点的亲和力可能较低，这与其对 ABCB1 的 ATP 酶活性无显著影响一致；然而，FW-04-806 可能与跨膜结构域中的底物结合位点结合更稳定，从而阻止抗癌药物从细胞中泵出。
FW-04-806 是一种具有抗肿瘤和逆转 MDR 作用的化合物，其抗肿瘤临床应用值得进一步研究。
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