Urupocidin C: a new marine guanidine alkaloid which selectively kills prostate cancer cells via mitochondria targeting

Abstract

New bicyclic guanidine alkaloid, urupocidin C (Ur-C) along with the previously known urupocidin A (Ur-A) were isolated from the rare deep-sea marine sponge Monanchora pulchra, harvested in Northwestern Pacific waters. The unique structure of Ur-C was elucidated using 1D and 2D NMR spectroscopy as well as mass spectra. We discovered a promising selectivity of both alkaloids for human prostate cancer (PCa) cells, including highly drug-resistant lines, compared to non-malignant cells. In cancer cells, marine derived compounds were able to induce G1-and S-cell cycle arrest as well as caspase-mediated cell death. For the first time we have identified mitochondrial targeting as a central mechanism of anticancer action for these and similar molecules. Thus, treatment with the isolated alkaloids resulted in mitochondrial membrane permeabilization consequently leading to the release of cytotoxic mitochondrial proteins to cellular cytoplasm, ROS upregulation, consequent activation of caspase-9 and-3, followed by PARP cleavage, DNA fragmentation, and apoptosis. Moreover, synergistic effects were observed when Ur-A and Ur-C were combined with clinically approved PARP inhibitor olaparib. Finally, these alkaloids exhibited additive effects in combination with docetaxel and androgen receptor inhibitor enzalutamide, both applied in PCa therapy. In conclusion, urupocidin-like compounds are promising lead molecules for the development of new drugs for the treatment of advanced pca. Marine sponges are well-known producers of novel small molecules possessing unique chemical structures and bearing promising biological properties 1,2. The need of self-defense against predators as well as competing species lead to the selection and accumulation of specific bioactive molecules (so-called secondary metabolites) used by the marine sponges and its symbiont organisms as a "chemical weapon" in this battle. The specific environmental conditions (low stable temperatures, high salinity and basic pH values of the ocean waters, lack of light etc.) stipulate a distinct biochemistry which leads to the production of secondary metabolites different from those biosynthesized by the terrestrial plants and animals 1. Due to the limited access, marine organisms and their metabolites are less studied in comparison with terrestrial animals and plants. However, the number of studies reporting new marine derived compounds possessing promising bioactivities is growing annually 3. To date approximately 10 drugs, which are based on small molecules or peptides isolated from marine organisms, are approved for clinical use-seven of those for anti-cancer therapy 3,4. Additionally, many more are currently in different stages of clinical and preclinical development 4-6. Marine sponges are considered as a primary source of many of these molecules as well as other materials like chitin and spongin, which are also used in biomedicine 7,8. However, due to the high

Marine natural products: the new generation of pharmacotherapeutics

“…55 For example, the guanidine alkaloid urupocidin A (Ur-A) has cytotoxic activity against different human cancer cell lines (Figure 1). 56 Ur-A inhibits an EGF-induced neoplastic transformation of epithelial cells. It induces a G2/M-phase cell cycle arrest and apoptosis of human cervical carcinoma HeLa cells.…”

“…57 A new bicyclic guanidine alkaloid, urupocidin C (Ur-C), along with the earlier known Ur-A, isolated from the rare deep-sea marine sponge Monanchora pulchra found in North-western Pacific waters exhibit acute selectivity for human prostate cancer cells and are believed to be a novel promising candidates as effective drugs against aggressive and drug resistant cancer of the prostate (Figure 1). 58 Neutrophils play an important role in acute inflammatory responses and recent studies have expanded their role to modulate chronic inflammatory and autoimmune diseases. Several types of chemical drugs are in use to treat inflammatory disorders, but with adverse side effects.…”

Recent Advances in Chemical Biology of Mitochondria Targeting

“…(D) Marine alkaloid sourced and guanidine-containing complex capable of targeting mitochondria. Image reproduced with permission, from Ref Dyshlovoy et al (2020) . (E) Snapshot of the permeation of Rh 19 derivative through bilayer lipid membrane (left panel) and schematic diagram of its mechanism (right panel, where R stands for a deprotonated neutral form, and RH + stands for a singly protonated cationic form).…”

“…Both guanidine and biguanide are delocalized lipophilic cationic molecules, which have a delocalized positive charge and therefore exhibit stronger lipophilicity than groups with a localized charge. Some studies have found that a new marine guarantin alkaloid can selectively kill prostate cancer cells and that the cytotoxic effect is related to mitochondrial targeting ( Dyshlovoy et al, 2020 ) ( Figure 3D ). This study confirmed for the first time that mitochondrial targeting is the central mechanism of the anti-cancer effect of these molecules and their derivatives.…”

Molecular-biological and biomedical investigations in FEB RAS. Some modern results and perspectives of the marine natural products studies

“…Эффективность этого действия повышалась при их применении с известным препаратом «Олапариб» и одним из основных противоопухолевых лекарств «Доцетаксел». Следовательно, урупоцидин С можно рассматривать в качестве лидерной молекулы для более детальных фармакологических исследований в экспериментальной и клинической онкологии [3].…”