Enterolactone and trabectedin suppress epithelial ovarian cancer synergistically via upregulating THBS1

Abstract

Epithelial ovarian cancer (EOC) is the most common and fatal subtype of ovarian malignancies, with no effective therapeutics available. Our previous studies have demonstrated extraordinary suppressive efficacy of enterolactone (ENL) on EOC. A chemotherapeutic agent, trabectedin (Trabe), is shown to be effective on ovarian cancer, especially when combined with other therapeutics, such as pegylated liposomal doxorubicin or oxaliplatin. Thrombospondin 1 (THBS1), a kind of matrix glycoprotein, plays important roles against cancer development through inhibiting angiogenesis but whether it is involved in the suppression of EOC by ENL or Trabe remains unknown. To test combined suppressive effects of ENL and Trabe on EOC and possible involvement of THBS1 in the anticancer activities of ENL and Trabe. The EOC cell line ES‐2 was transfected with overexpressed THBS1 by lentivirus vector. We employed tube formation assay to evaluate the anti‐angiogenesis activity of ENL and of its combined use with Trabe after THBS1 overexpression and established drug intervention and xenograft nude mouse cancer models to assess the in vivo effects of the hypothesized synergistic suppression between the agents and the involvement of THBS1. Mouse fecal samples were collected for 16S rDNA sequencing and microbiota analysis. We detected strong inhibitory activities of ENL and Trabe against the proliferation and migration of cancer cells and observed synergistic effects between ENL and Trabe in suppressing EOC. ENL and Trabe, given either separately or in combination, could suppress the tube formation capability of human microvascular endothelial cells, and this inhibitory effect became even stronger with THBS1 overexpression. In the ENL plus Trabe combination group, the expression of tissue inhibitor of metalloproteinases 3 and cluster of differentiation 36 was both upregulated, whereas matrix metalloproteinase 9, vascular endothelial growth factor, and cluster of differentiation 47 were all decreased. With the overexpression of THBS1, the results became even more pronounced. In animal experiments, combined use of ENL and Trabe showed superior inhibitory effects to either single agent and significantly suppressed tumor growth, and the overexpression of THBS1 further enhanced the anti‐cancer activities of the drug combination group. ENL and Trabe synergistically suppress EOC and THBS1 could remarkably facilitate the synergistic anticancer effects of ENL and Trabe.

Trabectedin and Lurbinectedin Modulate the Interplay between Cells in the Tumour Microenvironment—Progresses in Their Use in Combined Cancer Therapy

“…There is a pressing need to design combination treatments that may include conventional chemotherapeutic agents, immunologically targeted therapies such as immune checkpoint inhibitors (ICIs), or specific inhibitor molecules that target signaling or metabolic regulators, due to the complexity of tumoral biology and adaptation capacity, as well as resistance generation. In this sense, the field is experiencing a remarkable expansion: globally, TRB is assessed in combination with ICIs (antiPD-1/PD-L1 [ 107 , 108 , 109 , 110 ] and/or CTLA-4 [ 109 ]), monoclonal antibodies (-mAbs) that may act as either molecular inhibitors or activators, specific inhibitors of molecular targets (PARP [ 51 , 111 , 112 , 113 ], MDM2 [ 114 ], VEGF [ 115 , 116 , 117 ], CCR5 [ 118 ], m-TOR [ 119 ], IGF1-R [ 120 ], BCL2 [ 121 ], ATM/ATR [ 122 ],PPAR-γ [ 123 ], and CK-2/CLK2 [ 124 ]), recombinant proteins (shTRAIL [ 125 ]), topoisomerase inhibitors (irinotecan [ 126 , 127 , 128 , 129 , 130 , 131 ], topotecan [ 127 ], and camptothecin [ 132 ]), and immuno-modulatory biomolecules such as L19-mTNF [ 133 ] or dexamethasone [ 134 ], combined with propranolol [ 135 ], a β-adrenergic receptor inhibitor, or Wnt/β-catenin inhibitors [ 136 ] (PRI-724). It is combined with physical agents (hyperthermia [ 137 ] and radiation [ 138 , 139 , 140 , 141 ], among other strategies) as it is shown in Table 1 , where it is indicated in which pathologies and cel...…”