Combined arene ruthenium porphyrins as chemotherapeutics and photosensitizers for cancer therapy.
Mononuclear 5-(4-pyridyl)-10,15,20-triphenylporphyrin and 5-(3-pyridyl)-10,15,20-triphenylporphyrin as well as tetranuclear 5,10,15,20-tetra(4-pyridyl)porphyrin (tetra-4-pp) and 5,10,15,20-tetra(3-pyridyl)porphyrin) (tetra-3-pp) arene ruthenium(II) derivatives (arene is C(6)H(5)Me or p-Pr(i)C(6)H(4)Me) were prepared and evaluated as potential dual photosensitizers and chemotherapeutics in human Me300 melanoma cells. In the absence of light, all tetranuclear complexes were cytotoxic (IC(50) < or = 20 microM), while the mononuclear derivatives were not (IC(50) > or = 100 microM). Kinetic studies of tritiated thymidine and tritiated leucine incorporations in cells exposed to a low concentration (5 microM) of tetranuclear p-cymene derivatives demonstrated a rapid inhibition of DNA synthesis, while protein synthesis was inhibited only later, suggesting arene ruthenium-DNA interactions as the initial cytotoxic process. All complexes exhibited phototoxicities toward melanoma cells when exposed to laser light of 652 nm. At low concentration (5 microM), LD(50) of the mononuclear derivatives was between 5 and 10 J/cm(2), while for the tetranuclear derivatives LD(50) was approximately 2.5 J/cm(2) for the [Ru(4)(eta(6)-arene)(4)(tetra-4-pp)Cl(8)] complexes and less than 0.5 J/cm(2) for the [Ru(4)(eta(6)-arene)(4)(tetra-3-pp)Cl(8)] complexes. Examination of cells under a fluorescence microscope revealed the [Ru(4)(eta(6)-arene)(4)(tetra-4-pp)Cl(8)] complexes as cytoplasmic aggregates, whereas the [Ru(4)(eta(6)-arene)(4)(tetra-3-pp)Cl(8)] complexes were homogenously dispersed in the cytoplasm. Thus, these complexes present a dual synergistic effect with good properties of both the arene ruthenium chemotherapeutics and the porphyrin photosensitizer.
Schmitt
Frédéric
F
Institut Universitaire de Pathologie, CHUV, Bugnon 25, 1011, Lausanne, Switzerland.
Govindaswamy
Padavattan
P
Zava
Olivier
O
Süss-Fink
Georg
G
Juillerat-Jeanneret
Lucienne
L
Therrien
Bruno
B
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D047250:Calixarenes / Q000737:chemistry / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008027:Light; D008665:Metalloporphyrins / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D012428:Ruthenium / Q000737:chemistry / Q000627:therapeutic use*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008665:Metalloporphyrins; D017319:Photosensitizing Agents; D047250:Calixarenes; D012428:Ruthenium