Biologically Active Ganoderma Lucidum Compounds and Synthesis of Derivatives and Probes (SJ-19-0035)

St. Jude Reference #SJ-19-0035

Description

Researchers at St. Jude (and partner institutions) have characterized medicinal mushroom Ganoderma lucidum compounds with anti-cancer activity; improved derivatives and fluorescent probes.

Medicinal mushroom Ganoderma lucidum has been used in traditional Chinese medicine for more than two millennia. The Ganoderma lucidum extract (GLE) has been linked to improved length and quality of life, and it does not interfere with conventional therapy. Indeed, commercially available GLE is used in the prevention and treatment of hypertension, cancer, and immunological disorders. Furthermore, research suggests that GLE selectively inhibits breast cancer viability, induces apoptosis, reduces invasion, regulates key signaling molecules, and reduces tumor size by approximately 50% in mice xenografts.

Despite the well-established therapeutic uses of GLE, the organic compounds responsible for its biological activity had not been identified. The chemical characterization of the compounds responsible for the biological activity of GLE is imperative to design and test derivatives with improved efficacy and safety profiles.

Treatment options for triple negative breast cancer (TNBC) and inflammatory breast cancer (IBC), the most aggressive types of breast cancers, are very limited. Therefore, there is crucial unmet need to develop novel therapeutic agents to treat TNBC and IBC. It has been reported that the medicinal mushroom Ganoderma lucidum extract (GLE) has significant activity against breast cancer.

The present invention elucidated the chemical structure of the most abundant chemical constituents of GLE and determined their efficacy in different aggressive breast cancer models. Several natural compounds were identified and three showed significant anticancer activity (ergosterol, 5,6-dehydroergosterol, and ergoesterol peroxide). In particular, one of these compounds –ergoesterol peroxide– exerts selective effects on cancer cell viability, similar to the effects produced when using whole mushroom extract (GLE), suggesting an ample therapeutic window. Ergoesterol peroxide displays anti-proliferative effects through G1 phase cell cycle arrest, apoptosis induction via caspase 3/7 activation and PARP cleavage, decreases migration and invasion while inhibiting the expression of total AKT1, AKT2, BCL-XL, Cyclin D1 and c-Myc, induces ROS formation, and inhibits tumor growth in vivo.

This technology includes derivatives of ergosterol, 5,6-dehydroergosterol, and ergosterol peroxide with an-cancer activity. In particular, a derivative of ergoesterol peroxide –ergoesterol peroxide sulphonamide– showed superior potency against aggressive breast cancer. The derivatives comprise the methyl ester of ganoderic acid A, ergosterol sulfonamide, 5,6-dihydroergosterol sulfonamide, and ergoesterol peroxide sulfonamide. This technology further includes ergosterol peroxide chemical probes for in vitro anti-cancer evaluation, live cell studies, and proteomic profiling.

Benefits

  • Compounds with anti-cancer activities that have minimal effects on normal cells
  • The compounds induce reactive oxygen species (ROS), compromising cell fate
  • Derivatives with improved water solubility and ability to cross the cell membrane, favoring intracellular accumulation.
  • Therapeutic index greater than 10 for ergosterol peroxide sulfonamide
  • Fluorescent analogs of the compounds enable identification of biological targets and study of underlying mechanism
  • Fluorescent analogs of ergosterol peroxide were rationally designed to be spectrally orthogonal to organelle fluorescent trackers to enable colocalization studies

Applications

  • Development of therapies for aggressive malignancies such as triple negative and inflammatory breast cancers
  • Mechanistic studies using ergosterol peroxide chemical probes
  • Probe subcellular accumulation and interactions of ergosterol peroxide fluorescent probes
  • Probe the biological target of ergosterol peroxide using the chemical probes
  • Biotinylated probe of ergosterol peroxide to enable pull-down experiments for target identification.

 

Keywords

Ganoderma lucidum, florescent probe, hypertension, cancer, immunological disorders, breast cancer, apoptosis, tumor, triple negative breast cancer (TNBC), inflammatory breast cancer (IBC), ergoesterol peroxide, ergoesterol peroxide sulphonamide


 

Granted Patents or Published Applications

U.S. Provisional Patent Application No. 62/802,525 / Biologically Active Ganoderma Lucidum Compounds and Synthesis of Anti-cancer Derivatives; Ergosterol Peroxide Probes or Cellular Localization

International Patent Application No. PCT/US2020/017053 / Biologically Active Ganoderma Lucidum Compounds and Synthesis of Anti-cancer Derivatives; Ergosterol Peroxide Probes for Cellular Localization


 

Related Scientific References

Ling, Taotao, Walter H. Lang, Michelle M. Martinez-Montemayor, and Fatima Rivas. 2019. “Development of Ergosterol Peroxide Probes for Cellular Localisation Studies.” Organic & Biomolecular Chemistry 17(21): 5223–29.

Martinez-Montemayor, Michelle M. et al. 2019. “Identification of Biologically Active Ganoderma Lucidum Compounds and Synthesis of Improved Derivatives That Confer An-Cancer Activities in Vitro.” Frontiers in Pharmacology 10: 115.


 

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