James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Food Funct. 2017 Nov 15;8(11):4100-4107. doi: 10.1039/c7fo00882a.
Despite optimal diagnosis and early therapeutic interventions, the prognosis for ovarian cancer patients remains dismal because the efficacy of chemotherapy is limited by the development of resistance and off-site toxicity. Berry bioactives indicate preventive and therapeutic activities against various cancer types. Here, we examined the antiproliferative activity of berry anthocyanidins (Anthos) against drug-sensitive (A2780) and drug-resistant (A2780/CP70, OVCA432 and OVCA433) ovarian cancer cells. These drug-resistant ovarian cancer cell lines overexpress p-glycoproteins (PgP) and show >100-fold resistance to the chemotherapeutic drug cisplatin compared to A2780. We observed a dose-dependent growth inhibition of ovarian cancer cells with the Anthos. Furthermore, the treatment of drug-resistant ovarian cancer (OVCA433) cells with cisplatin in combination with the Anthos (75 μM) resulted in significantly higher cell killing. The cisplatin dose required to achieve this effect was 10 to 15-fold lower than the IC of cisplatin alone. However, many plant bioactives including Anthos face the challenge of poor oral bioavailability and stability. Recently, we have developed strategies to overcome these limitations by delivering Anthos via milk-derived exosomes. The exosomal Anthos (ExoAnthos) significantly enhanced the antiproliferative activity against the growth of ovarian cancer cells and inhibited tumor growth more efficiently compared to Anthos alone and a vehicle control. Often patients with cisplatin-resistant tumors retain sensitivity to paclitaxel (PAC). We prepared exosomal formulations of PAC (ExoPAC) for oral delivery as the systemic administration of PAC has severe side effects. ExoPAC delivered orally showed the same therapeutic efficacy as the free PAC delivered intraperitoneally. Finally, we report that the combination of the Anthos and PAC decreased the PgP level in a dose-dependent manner in OVCA432 cells. A significantly enhanced antitumor activity was observed with the combination of ExoPAC and ExoAnthos against A2780 tumor xenografts. Together, our data indicate that the berry Anthos are highly effective against ovarian cancer and that the milk exosomes serve as an excellent nano-carrier to enhance the drug's oral bioavailability for the management of ovarian cancer.
尽管进行了最佳诊断和早期治疗干预，卵巢癌患者的预后仍然不佳，因为化疗的疗效受到耐药性和非靶毒性的限制。浆果生物活性物质表明对各种癌症类型具有预防和治疗作用。在这里，我们研究了浆果花色苷（Anthos）对药物敏感（A2780）和耐药（A2780/CP70、OVCA432 和 OVCA433）卵巢癌细胞的抗增殖活性。这些耐药卵巢癌细胞系过度表达 p-糖蛋白（PgP），与 A2780 相比，对化疗药物顺铂的耐药性超过 100 倍。我们观察到卵巢癌细胞的生长抑制呈剂量依赖性。此外，用顺铂联合 Anthos（75μM）处理耐药卵巢癌细胞（OVCA433）导致细胞杀伤显著增加。达到这种效果所需的顺铂剂量比单独使用顺铂的 IC 低 10 到 15 倍。然而，包括 Anthos 在内的许多植物生物活性物质都面临着口服生物利用度和稳定性差的挑战。最近，我们通过使用牛奶衍生的外泌体来传递 Anthos 来克服这些限制。外泌体 Anthos（ExoAnthos）与单独的 Anthos 和载体对照相比，显著增强了对卵巢癌细胞生长的抗增殖活性，并更有效地抑制了肿瘤生长。通常，对顺铂耐药的肿瘤患者对紫杉醇（PAC）仍保持敏感性。我们为口服递送制备了 PAC 的外体制剂（ExoPAC），因为 PAC 的全身给药有严重的副作用。口服给予 ExoPAC 显示出与腹腔内给予游离 PAC 相同的治疗效果。最后，我们报告说，Anthos 和 PAC 的组合以剂量依赖的方式降低了 OVCA432 细胞中的 PgP 水平。在 A2780 肿瘤异种移植中，观察到 ExoPAC 和 ExoAnthos 的组合具有显著增强的抗肿瘤活性。总之，我们的数据表明浆果 Anthos 对卵巢癌非常有效，牛奶外体作为一种极好的纳米载体，可提高药物的口服生物利用度，用于卵巢癌的治疗。
