Elucidating the Multimodal Anticancer Mechanism of an Organometallic Terpyridine Platinum(II) N-Heterocyclic Carbene Complex against Triple-Negative Breast Cancer In Vitro and In Vivo

Abstract

Treatment of triple-negative breast cancer (TNBC) has long been a medical challenge because of the lack of effective therapeutic targets. Targeting lipid, carbohydrate, and nucleotide metabolism pathways has recently been proven as a promising option in view of three heterogeneous metabolic-pathway-based TNBC subtypes. Here, we present a multimodal anticancer platinum(II) complex, named Pt(II)caffeine, with a novel mode of action involving simultaneous mitochondrial damage, inhibition of lipid, carbohydrate, and nucleotide metabolic pathways, and promotion of autophagy. All these biological processes eventually result in a strong suppression of TNBC MDA-MB-231 cell proliferation both in vitro and in vivo. The results indicate that Pt(II)caffeine, influencing cellular metabolism at multiple levels, is a metallodrug with increased potential to overcome the metabolic heterogeneity of TNBC.

Developing a Ruthenium(III) Complex to Trigger Gasdermin E-Mediated Pyroptosis and an Immune Response Based on Decitabine and Liposomes: Targeting Inhibition of Gastric Tumor Growth and Metastasis

“…On one hand, it has been one of the most promising strategies for designing a novel next-generation anticancer metal agent by rational screening the metal ion and ligand to synthesize metal complexes; − on the other hand, the lipophilicity and anticancer activity of thiosemicarbazone compounds can be improved by modifying the hydrogen atom(s) at their N4 position with another group(s). ,− To obtain a new next-generation anticancer metal drug with high efficiency and low toxicity, we designed and synthesized a series of 2-hydroxy-1-naphthaldehyde thiosemicarbazone compounds by modifying the N3 position with an alkyl group or a phenyl group and then synthesized and characterized the corresponding Ru­(III) complexes. The crystal structures of Ru­(III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes ( 1b–4b ) were determined by X-ray crystallography (Figure ).…”

Synthesis and anticancer mechanisms of four novel platinum(ii) 4′-substituted-2,2′:6′,2′′-terpyridine complexes

“…† The Pt-Cl bond length (2.291(3)-2.305(3) Å) in tpy1Pt was different from those in tpy2Pt-tpy4Pt and other Pt(II)-terpyridyl complexes. [30][31][32][33][34][35][36][37][38][39][40][41][42]44 The Cambridge Crystallographic Data Centre (CCDC) numbers for PtS and tpy1Pt-tpy4Pt were 2281484-2281488. †…”

“…A series of coordination compounds based on terpyridyl and metals, such as copper( ii ), ruthenium( ii ), zinc( ii ), iridium( iii ), and rhenium( i ), 23–29 have been designed as antitumor drugs. 23–29 Among these, several Pt( ii )–terpyridyl complexes have been developed as important topoisomerase I/II inhibitors, 30 G-quadruplex DNA binders, 31 telomerase inhibitors, 32 DNA synthesis inhibitors, 33,34 reactive oxygen species (ROS) activators, 35 adenosine triphosphate (ATP) inhibitors, 36 mitochondrion-targeted agents, 37 photodynamic therapy agents, 38 autophagy–lysosomal system inductors, 39 and others drugs. 40–42 Nevertheless, the development of Pt( ii ) 4′-substituted-2,2′:6′,2′′-terpyridine (tpy1–tpy4) chemotherapeutics with mitophagy-targeting properties remains unexplored.…”

Developing a Gadolinium(III) Compound Based on Apoferritin for Targeted Magnetic Resonance Imaging and Dual-Modal Therapy of Cancer

“…Chemotherapy currently plays an important role in cancer treatments, but chemotherapy with a single mechanism is not enough to completely inhibit the growth of tumors and generally produces side effects in vivo . − Excitingly, chemotherapy combined with immunotherapy shows great promise for achieving better outcomes. − Recently, single-molecule theranostic agents have become highly desirable because theranostics realized by independently of diagnostic and therapeutic agents may lead to unsatisfied clinical outcomes and more serious side effects. − At present, gadolinium­(III) [Gd­(III)]-based magnetic resonance imaging (MRI) is a commonly used tool for diagnosing tumors in practice . Metal thiosemicarbazone compounds have been widely studied as promising antitumor agents in recent years due to their significant antitumor activity through integration of chemotherapy and immunotherapy. − Consequently, we decided to design a single-molecule Gd­(III) thiosemicarbazone compound based on the properties of Gd­(III) to realize the goals of MRI, chemotherapy, and immunotherapy.…”