Trabectedin

Trabectedin is a tetrahydroisoquinoline alkaloid with potent antitumor activity. Trabectedin can selectively inhibit transcription factors associated with DNA damage repair and block the DNA nucleotide excision repair pathway, leading to DNA double-strand breaks and tumor cell apoptosis. Trabectedin can also regulate the tumor microenvironment and indirectly exert antitumor effects by inhibiting the activity of tumor-associated macrophages. Trabectedin is often used in the study of soft tissue sarcoma and ovarian cancer ^[1-6].

Fifteen breast cancer samples were exposed to increasing concentrations of Trabectedin for 14 days, with dose-dependent tumor growth inhibition rates reaching 40%, 79%, and 100% at concentrations of 10nM, 100nM, and 1µM, respectively ^[5]. Prolonged exposure to Trabectedin induced a cytotoxic effect in 402.91 and 1765 cell lines, after 48 hours of continuous exposure to 2.5nM, cell death was 70% and 50%, respectively ^[6]. JN-DSRCT-1 cells are highly sensitive to increasing concentrations of Trabectedin (2.5nM, 24h), which induce a dose-dependent and transient G2/M cell cycle arrest ^[7].

In nude mouse models of MN/MCA1 fibrosarcoma, ID8 ovarian cancer, Lewis lung cancer, and MCA-fibrosarcoma, Trabectedin (0.15mg/kg, ip, 21d) modulates the tumor microenvironment by selectively targeting mononuclear phagocytes, especially tumor-associated macrophages (TAMs) and immunosuppressive myeloid suppressor cells (MDSCs), thereby exerting its antitumor efficacy ^[8]. In 4T1 cell and EMT6 TNBC models in BALB/c mice, Trabectedin (0.15mg/kg, ip, 15d) significantly slowed the growth of 4T1 and EMT6 tumors ^[9]. Treatment of C57BL/6J mice with Trabectedin (0.15mg/kg, ip, 42d) significantly reduced trabecular BV/TV and cortical BMD, while reducing serum P1NP as well as MS/BS and BFR/BS in mice, and inhibited mineralization and Runx2 gene expression in osteoblast culture ^[10].

References:
[1]. Takahashi N, Li W, Banerjee D, et al. Sequence-dependent synergistic cytotoxicity of ecteinascidin-743 and paclitaxel in human breast cancer cell lines in vitro and in vivo[J]. Cancer Research. 2002 Dec 1; 62(23): 6909-6915.
[2]. Atmaca H, Bozkurt E, Uzunoglu S, et al. A diverse induction of apoptosis by trabectedin in MCF-7 (HER2-/ER+) and MDA-MB-453 (HER2+/ER-) breast cancer cells[J]. Toxicology Letters. 2013 Aug 14; 221(2): 128-136
[3]. Cuevas C, Francesch A. Development of Yondelis (trabectedin, ET-743). A semisynthetic process solves the supply problem[J]. Natural Product Reports. 2009 Mar; 26(3): 322-337.
[4]. Carter NJ, Keam SJ. Trabectedin: a review of its use in the management of soft tissue sarcoma and ovarian cancer[J]. Drugs. 2007; 67(15): 2257-2276.
[5] D'Incalci M, Zambelli A. Trabectedin for the treatment of breast cancer[J]. Expert Opinion on Investigational Drugs. 2016; 25(1): 105-115
[6]. Germano G, Frapolli R, Simone M, et al. Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells[J]. Cancer Research. 2010 Mar 15; 70(6):2235-2244.
[7]. Uboldi S, Craparotta I, Colella G, et al. Mechanism of action of trabectedin in desmoplastic small round cell tumor cells[J]. BMC Cancer. 2017 Feb 6; 17(1): 107.
[8]. Germano G, Frapolli R, Belgiovine C, et al. Role of macrophage targeting in the antitumor activity of trabectedin[J]. Cancer Cell. 2013 Feb 11; 23(2): 249-262.
[9]. Schwarz E, Savardekar H, Zelinskas S, et al. Trabectedin Enhances the Antitumor Effects of IL-12 in Triple-Negative Breast Cancer[J]. Cancer Immunology Research. 2025 Apr 2; 13(4): 560-576.
[10]. Sinder BP, Zweifler L, Koh AJ, et al. Bone Mass Is Compromised by the Chemotherapeutic Trabectedin in Association With Effects on Osteoblasts and Macrophage Efferocytosis[J]. Journal of Bone and Mineral Research. 2017 Oct; 32(10): 2116-2127.

Trabectedin是一种具有强效抗肿瘤活性的四氢异喹啉生物碱。Trabectedin可选择性抑制与DNA损伤修复相关的转录因子，并阻断DNA核苷酸切除修复通路，导致DNA双链断裂和肿瘤细胞凋亡。Trabectedin还能调节肿瘤微环境，通过抑制肿瘤相关巨噬细胞的活性间接发挥抗肿瘤作用。Trabectedin常用于软组织肉瘤和卵巢癌的研究 ^[1-6]。

15个乳腺癌样本暴露于浓度不断增加的Trabectedin（14d），剂量依赖性肿瘤生长抑制率分别在10nM、100nM和1µM浓度下达到40%、79%和100% ^[5]。长期暴露于Trabectedin的402.91和1765细胞系中会产生细胞毒性作用，在2.5nM浓度下持续暴露48h后，细胞死亡率分别为70%和50% ^[6]。JN-DSRCT-1细胞对浓度增加的Trabectedin（2.5nM，24h）高度敏感，这会诱导剂量依赖性和短暂性的G2/M细胞周期停滞 ^[7]。

在MN/MCA1纤维肉瘤、ID8卵巢癌、Lewis肺癌、MCA-纤维肉瘤裸鼠模型中，Trabectedin（0.15mg/kg，ip，21d）通过选择性靶向单核吞噬细胞，特别是肿瘤相关巨噬细胞（TAM）和免疫抑制性髓系抑制细胞（MDSC），调节肿瘤微环境，从而发挥其抗肿瘤功效 ^[8]。在BALB/c小鼠的4T1细胞和EMT6的TNBC模型中，Trabectedin（0.15mg/kg，ip，15d）显著减缓了4T1和EMT6肿瘤的生长 ^[9]。长期给予C57BL/6J小鼠Trabectedin（0.15mg/kg，ip，42d）可显著降低小梁BV/TV和皮质BMD，同时降低小鼠血清P1NP以及MS/BS和BFR/BS，并抑制成骨细胞培养中的矿化和Runx2基因表达 ^[10]。