McCubrey James A, Chappell William H, Abrams Stephen L, Franklin Richard A, Long Jacquelyn M, Sattler Jennifer A, Kempf C Ruth, Laidler Piotr, Steelman Linda S
Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Adv Enzyme Regul. 2011;51(1):152-62. doi: 10.1016/j.advenzreg.2010.09.002. Epub 2010 Oct 28.
We have isolated cell with the cancer initiating cell (CIC) phenotype from PC3 cells. The PC3/(CIC) cells are more resistant than the PC3/(BC) cells to chemotherapeutic drugs such as docetaxel which is used to treat prostate cancer. Thus these prostate CICs could lay dormant and persist even after chemotherapeutic drug treatment. Then when the chemotherapeutic drug is removed, they could potentially repopulate the original tumor site or metastize to a distant site. However, the prostate CICs were not significantly more resistant to drugs which target EGFR, NF-κB, Smo and the natural product genistein. Interesting the prostate CICs could be rendered more sensitive to docetaxel by inclusion of suboptimal doses of genistein, cyclopamine, and EGFR inhibitors. In contrast, addition of suboptimal amounts of genistein, cyclopamine, or EGFR inhibitors did not increase the sensitivity of the PC/(BC) cells to docetaxel. Similar results were observed when combination experiments were performed with cyclopamine and suboptimal doses of either genistein or docetaxel. The BC cells are usually more rapidly proliferating than the CICs. Thus the CICs are not as sensitive to docetaxel which targets replication. In contrast, the CICs could be rendered sensitive to docetaxel or cyclopamine by co-treatment with certain other drugs, including the natural product genistein which is present in the human diet of many people, especially Asians. Genistein is by itself only weakly toxic to prostate and other cancer cells. That is probably one of the big reasons that it can be used as a dietary supplement for prostate and breast cancers. It is clear from our studies that low doses of genistein can increase the sensitivity of prostate CICs to drugs such as docetaxel and cyclopamine, two drugs either used or under consideration for prostate cancer therapy.
我们已从PC3细胞中分离出具有癌症起始细胞（CIC）表型的细胞。PC3/（CIC）细胞比PC3/（BC）细胞对多西他赛等用于治疗前列腺癌的化疗药物更具抗性。因此，这些前列腺CIC可能处于休眠状态，即使在化疗药物治疗后仍能持续存在。然后，当去除化疗药物时，它们可能会重新占据原来的肿瘤部位或转移到远处。然而，前列腺CIC对靶向表皮生长因子受体（EGFR）、核因子κB（NF-κB）、 smoothened（Smo）和天然产物染料木黄酮的药物并没有明显更强的抗性。有趣的是，通过加入次优剂量的染料木黄酮、环杷明和EGFR抑制剂，前列腺CIC对多西他赛可能会变得更敏感。相比之下，加入次优量的染料木黄酮、环杷明或EGFR抑制剂并没有增加PC/（BC）细胞对多西他赛的敏感性。当用环杷明与次优剂量的染料木黄酮或多西他赛进行联合实验时，也观察到了类似的结果。BC细胞通常比CIC增殖更快。因此，CIC对靶向复制的多西他赛不太敏感。相比之下，通过与某些其他药物共同处理，CIC对多西他赛或环杷明可能会变得敏感，这些药物包括许多人（尤其是亚洲人）饮食中存在的天然产物染料木黄酮。染料木黄酮本身对前列腺和其他癌细胞的毒性较弱。这可能是它可作为前列腺癌和乳腺癌膳食补充剂的一大重要原因。从我们的研究中可以清楚地看出，低剂量的染料木黄酮可增加前列腺CIC对多西他赛和环杷明等药物的敏感性，这两种药物已用于或正在考虑用于前列腺癌治疗。
