A Pt(IV) Prodrug Combining Chlorambucil and Cisplatin: A Dual-Acting Weapon for Targeting DNA in Cancer Cells

Abstract

In this study, two DNA-targeting agents, cisplatin and chlorambucil, were combined in a Pt(IV) prodrug, 1, which was thoroughly characterized by means of spectroscopic and spectrometric techniques. Tested towards a panel of various human tumor cell lines, this compound showed superior in vitro antitumor potential than the reference drug cisplatin. In addition, an antitumor potential of 1 was found, which is comparable to that of oxaliplatin in 3D spheroid models of colon cancer cells. Mechanistic studies performed in colon cancer cells confirmed that the conjugation of chlorambucil to Pt(IV) cisplatin-based scaffold tunes the lipophilicity of the prodrug, consequently improving the ability of the compound to accumulate into cancer cells and to target DNA, ultimately leading to apoptotic cancer cell death.

Potent Chlorambucil-Platinum(IV) Prodrugs

“…A positive aspect of this design is that these platinum(IV) derivatives containing CLB in the axial position exhibited longer retention times with almost no untargeted toxicities in vivo [ 51 ]. Furthermore, Montagner et al undertook a similar investigation with findings that supported the claims of Ma et al and Qin et al, and established that the CLB effectively tunes the lipophilicity of the platinum(IV) prodrug [ 53 ]. Lipophilicity plays an important role in terms of fighting cisplatin-resistant cancer cells, as it improves cellular uptake properties and it is hypothesized to facilitate passive diffusion through the cell membranes [ 26 ].…”

Gd(iii)–Pt(iv) theranostic contrast agents for tandem MR imaging and chemotherapy

“…[15][16][17][18][19] A variety of groups can be incorporated as axial ligands to allow for tumor targeting, combination therapy, bioimaging, and controlled reduction of the Pt(IV). [20][21][22][23][24][25][26][27][28][29][30][31] Sessler and coworkers were the rst to demonstrate how Gd(III) complexes can be used synergistically with Pt(IV) prodrugs. Their Gd(III)-texaphyrin complexes have been used to increase tumor localization and mediate the reduction of Pt(IV) to Pt(II).…”

The Increase in the Drug Resistance of Acute Myeloid Leukemia THP-1 Cells in High-Density Cell Culture Is Associated with Inflammatory-like Activation and Anti-Apoptotic Bcl-2 Proteins

“…The increase in drug resistance in leukemic cells in high-density cultures was marked earlier [ 50 , 51 ]; however, the mechanism of this phenomena remains unclear. The results of our work show the great increase in the resistance of different AML cells (lines HL-60, THP-1, MV411, U937) in high-density cultures to inhibitors of topoisomerases, etoposide and topotecan [ 52 , 53 ]; an antimetabolite, cytarabine [ 54 ]; DNA targeting antitumor drugs doxorubicin and cisplatin [ 55 , 56 , 57 ]; as well as to antitumor recombinant protein izTRAIL [ 58 ]. It was important that the increase in the drug resistance of AML cells in high-density cell culture was reversible and that the transfer of the AML cells from high-density to low-density cultures decreased the resistance to an initial state.…”