2. Academic Validation
  3. The tetrahydroxanthone-dimer phomoxanthone A is a strong inducer of apoptosis in cisplatin-resistant solid cancer cells

The tetrahydroxanthone-dimer phomoxanthone A is a strong inducer of apoptosis in cisplatin-resistant solid cancer cells

  • Bioorg Med Chem. 2019 Oct 1;27(19):115044. doi: 10.1016/j.bmc.2019.115044.
Chenyin Wang 1,  Laura Engelke 1,  David Bickel 1,  Alexandra Hamacher 1,  Marian Frank 2,  Peter Proksch 2,  Holger Gohlke 3,  Matthias U Kassack 4
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • 2 Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine Universität Düsseldorf, 40225 Düsseldorf, Germany.
  • 3 Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany; John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC) & Institute for Complex Systems - Structural Biochemistry (ICS 6), Forschungszentrum Jülich GmbH, 52425 Jülich, Germany.
  • 4 Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany. Electronic address: matthias.kassack@uni-duesseldorf.de.
PMID: 31443950 DOI: 10.1016/j.bmc.2019.115044
Abstract

Platinum compounds are the first-line therapy for many types of Cancer. However, drug resistance has frequently been reported for and is a major limitation of platinum-based chemotherapy in the clinic. In the current study, we examined the anti-tumor activity of phomoxanthone A (PXA), a tetrahydroxanthone dimer isolated from the endophytic fungus Phomopsis longicolla, in several solid Cancer cell lines and their cisplatin-resistant sub-cell lines. PXA showed strong cytotoxic effects with IC50 values in the high nanomolar or low micromolar range in MTT assays. IC50 values of PXA were lower than those of cisplatin. Remarkably, equipotent anti-cancer activity was found in cisplatin-sensitive and respective cisplatin-resistant cells. Anticancer effects of PXA were studied in further detail in ovarian Cancer (A2780) and bladder Cancer (J82) cell pairs. PXA led to rapid depolarization of the mitochondrial membrane potential and strong activation of Caspase 3 and 7, eventually resulting in strong induction of Apoptosis. These effects occurred again both in sensitive and resistant cell lines. IC50 values of PXA from MTT and mitochondrial membrane depolarization assays were in good agreement. Configurational free energy computations indicate that both the neutral and singly negatively charged PXA show membrane partitioning and can penetrate the inner mitochondrial membrane. PXA treatment did not damage the plasma membranes of Cancer cells, thus excluding unspecific membrane effects. Further, PXA had neither an effect on intracellular ROS nor on reduction of ROS after hydrogen peroxide treatment. In conclusion, our studies present PXA as a natural compound with strong apoptotic Anticancer effects against platinum-resistant solid cancers. This may open new treatment options in clinically resistant malignancies.

Keywords

Apoptosis; Caspase activation; Cisplatin resistance; Configurational free energy computations; Mitochondrial membrane potential; Phomoxanthone A.

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