Doxorubicin (Dox) is one of the most successful anticancer drugs in use. However, chemoresistance is one of the main limitations that patients face. Therefore, development of new strategies to improve the efficacy of Dox is needed. Marine‐derived fungi are especially promising sources of new anticancer compounds. In this work, antitumor activity of crude ethyl extract of the cultures of the marine‐derived fungus Neosartorya siamensis KUFA 0017 (NS), combined with Dox, was evaluated in six cancer cell lines. To evaluate possible mechanisms involved in the eventual improvement of Dox's cytotoxicity by NS extract, effects on DNA damage, cell death, ultrastructural modifications, and intracellular accumulation of Dox were assessed. The NS extract demonstrated a significant enhancement of Dox's cytotoxic activity in A549 cells, inducing DNA damage, cell death, and intracellular accumulation of Dox. Additionally, the cytotoxic effect of eight compounds, isolated from this extract, that is, 2,4‐dihydroxy‐3‐methylacetophenone‐(C1), nortryptoquivaline‐(C2), chevalone C‐(C3), tryptoquivaline H‐(C4), fiscalin A‐(C5), epi‐fiscalin‐C (C6), epi‐neofiscalin A‐(C7), and epi‐fiscalin A‐(C8), alone and combined with Dox was also evaluated in lung cancer cells. The cytotoxic effect of Dox was potentiated by all the isolated compounds (except C1) in A549 cells. Therefore, we concluded that NS extract potentiated cytotoxicity by inhibiting cell proliferation, increasing intracellular accumulation of Dox, and inducing cell death (possibly by an autophagic process). The isolated compounds also enhanced the activity of Dox, supporting the potential of this sort of combination. These data call for further studies to characterize drug interactions and underlying mechanisms.

中文翻译：

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海洋源真菌新沙门氏菌 KUFA 0017 提取物及其次生代谢产物能否增强阿霉素的抗肿瘤活性？一项体外调查揭示了对肺癌细胞的相互作用

多柔比星 (Dox) 是最成功的抗癌药物之一。然而，化学抗性是患者面临的主要限制之一。因此，需要开发新的策略来提高 Dox 的疗效。海洋来源的真菌是新型抗癌化合物的特别有前途的来源。在这项工作中，在六种癌细胞系中评估了海洋来源真菌 Neosartorya siamensis KUFA 0017 (NS) 培养物的粗乙基提取物与 Dox 的抗肿瘤活性。为了评估 NS 提取物最终改善 Dox 细胞毒性的可能机制，评估了对 DNA 损伤、细胞死亡、超微结构修饰和 Dox 细胞内积累的影响。NS 提取物证明了 Dox 在 A549 细胞中的细胞毒活性显着增强，诱导 DNA 损伤、细胞死亡和 Dox 的细胞内积累。此外，从该提取物中分离出的 8 种化合物的细胞毒性作用，即 2,4-二羟基-3-甲基苯乙酮-(C1)、去甲喹啉-(C2)、chevalone C-(C3)、tryptoquivaline H-(C4)还在肺癌细胞中评估了单独和与 Dox 联合使用的 fiscalin A-(C5)、epi-fiscalin-C (C6)、epi-neofiscalin A-(C7) 和 epi-fiscalin A-(C8)。Dox 的细胞毒作用在 A549 细胞中被所有分离的化合物（C1 除外）增强。因此，我们得出结论，NS 提取物通过抑制细胞增殖、增加 Dox 的细胞内积累和诱导细胞死亡（可能通过自噬过程）来增强细胞毒性。分离的化合物还增强了 Dox 的活性，支持了这种组合的潜力。