Enriching cancer pharmacology with drugs of marine origin

Abstract

Marine natural products have proven, over the last half-century, to be effective biological modulators. These molecules have revealed new targets for cancer therapy as well as dissimilar modes of action within typical classes of drugs. In this scenario, innovation from marine-based pharmaceuticals has helped advance cancer chemotherapy in many aspects, as most of these are designated as first-in-class drugs. Here, by examining the path from discovery to development of clinically approved drugs of marine origin for cancer treatment-cytarabine (Cytosar-U®), trabectedin (Yondelis®), eribulin (Halaven®), brentuximab vedotin (Adcetris®), and plitidepsin (Aplidin®)- together with those in late clinical trial phases-lurbinectedin, plinabulin, marizomib, and plocabulin-the present review offers a critical analysis of the contributions given by these new compounds to cancer pharmacotherapy.

Figure 1

Marine natural products and their derivatives of pharmacological relevance. In the box, the tetrahydroisoquinoline rings (pink)—in which both A and B rings have been proven essential for bioactivity due to their involvement in the interaction with DNA minor groove—are highlighted in the chemical structure of trabectedin. For lurbinectedin, further noteworthy chemical features particularly found in marine natural products are emphasized, such as stereochemical carbons (blue spheres), complex intra‐cyclization, and a high number of heteroatoms generating different chemical functions comprising oxygen (red), nitrogen (green), and sulphur (orange) atoms

Figure 2

Overview of the multiple mechanisms of action of anticancer marine drugs in clinical use. Inhibition of the respective molecular targets by plitidepsin (upper left), trabectedin (lower left), eribulin (upper right), and ADCetris® (lower right) triggers tumour cell stress, which culminates in cell death by apoptosis. Plitidepsin hinders the pro‐oncogenic function of eukaryotic elongation factor 1A2 (eEF1A2), which impairs transportation of misfolded proteins to the proteasome and causes accumulation of non‐functional proteins. Additionally, by inhibiting eEF1A2, it further blocks activation of the aggresome and, therefore, prevents protein digestion by autophagy. The marked accumulation of non‐functional proteins leads to cell death by apoptosis. Trabectedin is a DNA‐alkylating agent that specifically inhibits the activity of RNA polymerase II, thus not affecting basal transcription. The selective inhibition of transcription induced by trabectedin decreases the levels of P‐glycoprotein, assuring a potent cytotoxicity against resistant tumours. Modulation of tumour micro‐environment is a valuable and interesting feature of this compound, which is attained by the specific depletion of macrophages (Mϕs), tumour‐associated macrophages (TAMs), and circulating monocytes (Mos) by apoptosis. Eribulin is an antitubulin agent that blocks tubulin polymerization, further leading to cell cycle arrest and mitotic catastrophe. Additionally, eribulin induces the formation of non‐functional tubulin aggregates and triggers apoptosis. ADCetris, an antibody‐drug conjugate (ADC), is selectively recognized and internalized by CD30+ cells through endocytosis. The warhead, monomethyl auristatin E, is released into the cytosol after digestion in endolysosomes and blocks tubulin polymerization, causing persistent mitotic arrest and induction of apoptosis. Furthermore, ADCetris also induces antibody‐dependent cellular phagocytosis (ADCP) by Mϕs via Fc‐FcγR binding

Figure 3

Milestones of anticancer drugs from marine origin on the market. The length of time between the isolation of the natural molecule and the approval of the commercial product was 17 years for trabectedin (Yondelis®), 22 years for dihydrodidemin B (Aplidin®), 24 years for halichondrin (Halaven®), and 24 years for dolastatin (ADCetris®)