Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity

Abstract

Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep water sponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity towards the pancreatic cancer cell lines AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apoptosis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulin containing microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1 showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affect tubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls. The anti-tumor activities of leiodermatolide, as well as the proven utility of anti-mitotic compounds against cancer, make leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research.

Strategy Evolution in the Total Synthesis of (−)‐Leiodermatolide

“…Inevitably, NMR analysis takes the minority of the time and reveals the majority of the structural information, but relies on synthetic efforts to fill in the gaps. Going forward, the development of a practical total synthesis of leiodermatolide should enable access to both a sustainable supply and designed analogs for further evaluation of this promising new experimental antimitotic drug in cancer chemotherapy ,…”

“…It was also suggested that leiodermatolide could be acting as a centrosome‐declustering agent, but this hypothesis requires verification. Preliminary evaluation in vivo in a mouse model of metastatic pancreatic cancer led to a significant reduction in tumour size, underscoring leiodermatolide's clinical potential as a new experimental chemotherapeutic lead for pancreatic and other solid tumours …”

Bioactive Compounds in the Ethanol Extract of Marine Sponge Stylissa carteri Demonstrates Potential Anti-Cancer Activity in Breast Cancer Cells

“…Despite advanced BC treatment modalities are available, advanced stage of BC patients, develop resistant to current therapeutic options. Chemotherapy resistance leads into cancer progression and metastasis, thereby it remains as the greatest challenges in cancer management compound demonstrates a powerful anti-tumor activity compared to paclitaxel in prostate cancer cells (Guzmán et al, 2016). Above data indicating that sponges are very potential to be studied for novel anti-cancer drug discovery.…”

Identifying Toxic Impacts of Metals Potentially Released during Deep-Sea Mining—A Synthesis of the Challenges to Quantifying Risk

“…Indeed, the provision of Ecosystem Services has been argued as one standard for assessing "serious harm" in the context of DSM Environmental Impact Assessments (EIAs) (Le et al, 2017), because these services link environmental health to human wellbeing. Provisioning Services include supporting fisheries for human nutrition (e.g., Gordon, 2001) and novel natural products (e.g., Guzman et al, 2016), whilst Regulating Services include the absorption of carbon from the atmosphere and its subsequent sequestration with the deep ocean interior and within the seabed (e.g., Vardaro et al, 2009). At the sea floor diverse and stable biological communities represent a biodiversity resource which provides a reservoir of biological and genetic resources that might present the source of future natural products of further benefit to human kind (Harden-Davies, 2017).…”