Cellular Response to Antitumor cis-Dichlorido Platinum(II) Complexes of CDK Inhibitor Bohemine and Its Analogues
The cellular and molecular pharmacology of the new class of anticancer drugs, in which the CDK inhibitor bohemine and its analogues are coordinated to Pt(II) to form cisplatin derivatives, was investigated. The results revealed the unique anticancer profile of a cisplatin-derived platinum(II) dichlorido complex involving N(7)-coordinated bohemine (C1). Although the IC50 values were similar to 6-fold higher for C1 than for cisplatin in cisplatin-sensitive tumor cells, the tumor cells in which C1 was also active are those which acquired resistance to cisplatin. In addition, among the novel conjugates of bohemine and its analogues with cisplatin, marked selectivity of C1 for tumor cells relative to the nontumorigenic, normal cells was observed. However, coordination of bohemine to platinum in C1 considerably reduced one of the dual functionalities anticipated to be effective after C1 reaches the nucleus. Further studies performed in the cells with wt p53 status show differences between cisplatin and C1 at the level of cell cycle regulation. Impedance-based real-time monitoring of the effects of C1 and cisplatin on cell growth supported the thesis that critical differences exist in the rate and mechanisms of cell kill caused by the two agents and that C1 was a more potent inducer of apoptosis and/or necrosis than cisplatin. The results also showed that the distinct differences in cell killing observed for C1 and cisplatin might be associated with processes at the DNA level. The DNA binding experiments carried out in a cell-free medium demonstrated that modification reactions resulting in the irreversible coordination of C1 to DNA were slower than that of cisplatin. Transcription mapping experiments and determination of interstrand cross-linking efficiency of C1 suggested that several aspects of DNA binding mode of C1 and cisplatin were similar. It was concluded that C1 remains a promising prototype of compounds for the generation of novel drug candidates with cytotoxicity profiles different from those of the platinum drugs currently in use.