Abstract:Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: "Multi-action" Pt(IV) derivatives of cisplatin with combretastatin A4 (CA4) bioactive ligands that are conjugated to Pt(IV) by carbonate are unique because the ligand (IC 50 < 10 nM) is dramatically 1000-folds more cytotoxic than cisplatin in vitro. The Pt(IV)-CA4 prodrugs were as cytotoxic as CA4 itself, indicating that the platinum moiety probably plays an insignificant role in triggering cytotoxicity, suggesting that the Pt(IV)-CA4 … Show more
“…This has for instance been observed for some Pt( iv ) derivatives with combretastatin A4 bioactive ligands, where the metal was a thousand fold less cytotoxic than the organic moiety. 371 This, and the usually complex synthesis, overall limits the efficacy and clinical translation of multi-action complexes. By employing nanocarriers for combination therapies, these challenges can be addressed to some extent.…”
“…This has for instance been observed for some Pt( iv ) derivatives with combretastatin A4 bioactive ligands, where the metal was a thousand fold less cytotoxic than the organic moiety. 371 This, and the usually complex synthesis, overall limits the efficacy and clinical translation of multi-action complexes. By employing nanocarriers for combination therapies, these challenges can be addressed to some extent.…”
“…Combretastatin A-4 (CA4), an tubulin polymerization inhibitor that exhibits dramatically 1000-folds more cytotoxic than cisplatin, was conjugated with Pt(IV) ( 14 ). CA4 showed higher cytotoxicity than Pt(IV)-CA4 conjugates in vitro , while in vivo test showed that Pt(IV)-CA4 conjugates exhibited significantly enhanced tumor suppression and reduced acute toxicity (weight loss) in LLC-bearing mice ( Schmidt et al, 2021 ). Pt(IV)-bioactive ligand conjugates usually exerted synergistic anticancer activity via multi-action.…”
Section: Endo-stimuli-responsive Pt- and Ru-based Anticancer Drugsmentioning
Lung cancer is the most common cause of cancer-related deaths worldwide. More efficient treatments are desperately needed. For decades, the success of platinum-based anticancer drugs has promoted the exploration of metal-based agents. Four ruthenium-based complexes have also entered clinical trials as candidates of anticancer metallodrugs. However, systemic toxicity, severe side effects and drug-resistance impeded their applications and efficacy. Stimuli-responsiveness of Pt- and Ru-based complexes provide a great chance to weaken the side effects and strengthen the clinical efficacy in drug design. This review provides an overview on the stimuli-responsive Pt- and Ru-based metallic anticancer drugs for lung cancer. They are categorized as endo-stimuli-responsive, exo-stimuli-responsive, and dual-stimuli-responsive prodrugs based on the nature of stimuli. We describe various representative examples of structure, response mechanism, and potential medical applications in lung cancer. In the end, we discuss the future opportunities and challenges in this field.
The
base excision repair (BER) pathway is essential for cancer
cells to resist chemotherapeutic treatment, but its significance is
underrated. The present study describes a novel Pt(IV) prodrug, AP1, targeting a critical BER protein, apurinic/apyrimidinic
endonuclease 1 (APE1). AP1 induces intracellular accumulation
of platinum and activates DNA damage response and apoptosis signals. AP1 can strongly inhibit the growth of malignant cells, including
cisplatin-resistant cancer cells, with up to 18.11 times inhibition
compared with cisplatin. Moreover, it is as toxic to normal cells
as cisplatin. In a xenograft model, AP1 is 3.86-fold
more potent than cisplatin without adverse effects. Intriguingly, AP1 can directly inhibit the AP endonuclease activity of APE1,
leading to an interruption of miRNA processing and upregulation of
the tumor suppressor PTEN. Our findings shed light on a mode of Pt(IV)
interaction with a target protein and highlight the critical role
of BER in platinum-based cancer treatment.
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