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Review
. 2024 Jan 9;29(2):331.
doi: 10.3390/molecules29020331.

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

Adrián Povo-Retana  1 , Rodrigo Landauro-Vera  1 , Carlota Alvarez-Lucena  1 , Marta Cascante  2   3 , Lisardo Boscá  1   4
Affiliations
Review

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

Adrián Povo-Retana et al. Molecules. .

Abstract

Trabectedin (TRB) and Lurbinectedin (LUR) are alkaloid compounds originally isolated from Ecteinascidia turbinata with proven antitumoral activity. Both molecules are structural analogues that differ on the tetrahydroisoquinoline moiety of the C subunit in TRB, which is replaced by a tetrahydro-β-carboline in LUR. TRB is indicated for patients with relapsed ovarian cancer in combination with pegylated liposomal doxorubicin, as well as for advanced soft tissue sarcoma in adults in monotherapy. LUR was approved by the FDA in 2020 to treat metastatic small cell lung cancer. Herein, we systematically summarise the origin and structure of TRB and LUR, as well as the molecular mechanisms that they trigger to induce cell death in tumoral cells and supporting stroma cells of the tumoral microenvironment, and how these compounds regulate immune cell function and fate. Finally, the novel therapeutic venues that are currently under exploration, in combination with a plethora of different immunotherapeutic strategies or specific molecular-targeted inhibitors, are reviewed, with particular emphasis on the usage of immune checkpoint inhibitors, or other bioactive molecules that have shown synergistic effects in terms of tumour regression and ablation. These approaches intend to tackle the complexity of managing cancer patients in the context of precision medicine and the application of tailor-made strategies aiming at the reduction of undesired side effects.

Keywords: adaptative immunity; combined therapies; ecteinascidins; innate immunity; lurbinectedin; lymphocytes; macrophages; molecular oncology; trabectedin.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 2
Figure 2
Molecular structure of trabectedin [14] (A) and lurbinectedin [18] (B).
Figure 1
Figure 1
Ecteinascidia turbinata, the ascidian source for trabectedin and lurbinectedin (Courtesy of PharmaMar S.A., Madrid, Spain).
Figure 3
Figure 3
Immunometabolic and functional response of human macrophages to trabectedin and lurbinectedin. Glycolysis and the pentose phosphate pathway (PPP) are favoured, and serine production is predicted by RNAseq and fluxomic approaches [96].
Figure 4
Figure 4
Reported molecular mechanisms for TRB and LUR in tumour cells, the tumour microenvironment, and immune cells. TRB and LUR are DNA intercalating molecules and transcriptional regulators. They impact human TAM biology acting as TME regulators and immunomodulate human immune response and activation.
See this image and copyright information in PMC

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