The gallium complex KP46 exerts strong activity against primary explanted melanoma cells and induces apoptosis in melanoma cell lines
- Author(s)
- Seied Mojtaba Valiahdi, Petra Heffeter, Michael Jakupec, Rodrig Marculescu, Walter Berger, Klemens Rappersberger, Bernhard Keppler
- Abstract
The antineoplastic properties of gallium are well documented. Due to their robust accumulation of gallium, melanoma cells should be amenable to gallium-based anticancer drugs. With the aim of improving the disappointingly low activity of inorganic gallium salts, we have developed the orally bioavailable gallium complex KP46 that was already successfully studied in a phase I clinical trial. In order to assess its therapeutic potential in malignant melanoma, its antiproliferative effects were investigated in series of human cell lines and primary explanted melanoma samples by means of the MTT assay and the Human Tumor Cloning Assay, respectively. When compared with other cell lines, the majority of melanoma cells rank among the KP46-sensitive cell lines (IC50 values: 0.8¿3.7 µM). Clinically achievable concentrations of KP46 proved to be highly effective in melanoma cells from primary explants of cutaneous and lymph node metastases. Colony growth was inhibited in 10/10 specimens by 5 µM KP46 (corresponding to the steady-state plasma concentration previously measured in a study patient) and in 4/10 specimens by 0.5 µM KP46. In vitro potency of KP46 is higher than that of dacarbazine or fotemustine and comparable with that of cisplatin. The effects induced by KP46 in melanoma cell lines involve cell cycle perturbations (S phase arrest) and apoptosis (activation of caspase-9, PARP cleavage, formation of apoptotic bodies). No effects on DNA secondary structure could be observed in an electrophoretic mobility shift assay using double-stranded plasmid DNA. Thus, further studies on the therapeutic applicability of KP46 in malignant melanoma are warranted.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- Medizinische Universität Wien, Krankenanstalt Rudolfstiftung
- Journal
- MELANOMA RESEARCH
- Volume
- 19
- Pages
- 283-293
- No. of pages
- 11
- ISSN
- 0960-8931
- DOI
- https://doi.org/10.1097/CMR.0b013e32832b272d
- Publication date
- 2009
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 302011 Dermatology, 301904 Cancer research
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/c2959628-7443-4d20-8cf6-baadd6299dd7