Effects of a combretastatin A4 analogous chalcone and its Pt-complex on cancer cells: A comparative study of uptake, cell cycle and damage to cellular compartments.
The combretastatin A4 analogous chalcone (2E)-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 1 and its dichloridoplatinum(II) (6-aminomethylnicotinate) complex 2 were previously found to be highly active against a variety of cancer cell lines while differing in their apoptosis induction and long-term regrowth retardation (Schobert et al. [1]). Further differences were identified now. The cellular uptake of complex 2, like that of oxaliplatin, occurred mainly via organic cation transporters (OCT-1/2; ∼32%) and copper transporter related proteins (Ctr1; ∼24%), whereas that of chalcone 1 was dependent on endocytosis (∼80%). Complex 2 was more tumour-specific than 1 concerning neural cells. This was apparent from the ratios of IC(50)(48h) values against primary astrocytes versus human glioma cells U87 (>7000 for complex 2; 55 for compound 1). In tubulin-rich neurons and 518A2 melanoma cells complex 2 disrupted microtubules and actin filaments. Cancer cells treated with 2 could repair the cytoskeletal damage but ceased to proliferate and perished. Complex 2 was particularly cytotoxic against P-gp-rich cells. It acted as a substrate for ABC-transporters of types BCRP, MRP3, and MRP1 and so was less active against the corresponding cancer cell lines. Complex 2 arrested the cell cycle of the melanoma cells in G(1) and G(2)/M phases. A fragmentation of their Golgi apparatus was observed by TEM for incubation with complex 2 but not with 1. In conclusion, unlike chalcone 1, its platinum complex 2 is highly cell line specific, is taken up via cell-controlled transporters and induces apoptosis by triggering multiple targets.
Zoldakova
Miroslava
M
Organic Chemistry Laboratory, University of Bayreuth, Universitätsstrasse 30, D-95440 Bayreuth, Germany.
Kornyei
Zsuzsanna
Z
Brown
Andreas
A
Biersack
Bernhard
B
Madarász
Emília
E
Schobert
Rainer
R
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D022082:Cellular Structures / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D047188:Chalcones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013267:Stilbenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D047188:Chalcones; D027701:Organic Cation Transport Proteins; D009944:Organoplatinum Compounds; D013267:Stilbenes; C058728:fosbretabulin