Novel Indole–Chalcone Derivative-Ligated Platinum(IV) Prodrugs Attenuate Cisplatin Resistance in Lung Cancer through ROS/ER Stress and Mitochondrial Dysfunction

Abstract

Developing multifunctional platinum(IV) prodrugs via integrating bioactive pharmacophores into one entity is an attractive strategy to ameliorate the defects of platinum(II) drugs. Herein, a series of indole–chalcone derivative-ligated platinum(IV) complexes were synthesized and evaluated for their anticancer activities. Among them, optimal complex 17a exerted superior activity compared to that of cisplatin (CDDP) against the tested cells but showed lower cytotoxicity toward human normal lung cells. Detailed mechanisms demonstrated that 17a significantly enhanced intracellular accumulation, induced DNA damage, and inhibited migration in A549/CDDP cells. Furthermore, 17a efficiently disturbed the tubulin–microtubule system, initiated reactive oxygen species (ROS)-mediated endoplasmic reticulum stress, and activated a mitochondrion-dependent apoptosis signaling pathway. Besides, 17a was superior to free drugs or their combination in inhibiting cancer growth in A549/CDDP xenografts without inducing obvious side effects. The physical mixture of 16a and CDDP was almost identical to 17a but showed apparent systematic side effects. In summary, our studies may provide an efficient treatment regimen for CDDP resistance.

Ligustrazine-Derived Chalcones-Modified Platinum(IV) Complexes Intervene in Cisplatin Resistance in Pancreatic Cancer through Ferroptosis and Apoptosis

“…7,19 Therefore, to further investigate whether 16a could initiate mitochondrial apoptotic signaling pathway, we first study the effect of 16a on the changes of intracellular ROS generation via 2′,7′dichlorofluorescein diacetate (DCFH-DA) staining assays, using 14a, CDDP (5 μM), and combined group (14a + CDDP, 5 μM + 5 μM) as references. In line with our and others' reports, 7,19,32 CDDP was not able to increase the production of ROS in PANC-1/CDDP cells as compared with untreated group (Figure 5A,B). Besides, ROS levels in 14atreated group were 4.76-fold higher than those of the CDDPtreated group and were further elevated to 13.06-fold in the combined group, indicating that 14a and CDDP in combination were more potent to promote the ROS production.…”

“…The traces in Figure S4C,D revealed that 16a kept intact at 0 h treatment with AsA but was gradually reduced to another peak which appeared at the position of 14a along with the time process. In accordance with our and others’ reports, CDDP was not detected via HPLC. , However, the signals of CDDP ( m / z 299.0250) and hydrolyzed CDDP ( m / z 264.1563) were recorded via HR-MS (Figure S4H). Considering the acid condition of the tumor microenvironment, physiological condition, and biological medium, the stability of 16a in PBS (pH = 5.5 or 7.4) or DMEM (containing 10% fetal bovine serum) was measured.…”

“…In accordance with our and others' literatures, CDDP showed undifferentiated activity toward these cancer lines, with IC 50 values in the micromolar range, whereas those of the platinum(IV) complex were in two-digit micromolar range. 32,34 Moreover, enhanced activities of compounds 15a−15c or 16a−16c were found upon introduction compounds 13a−13c or 14a−14c into axial hydroxyl groups of platinum(IV) complexes, proving that axial ligands could efficiently alter the anti-proliferative effects of platinum(IV). Besides, the physical mixture of CDDP and 14a obtained superior anti-proliferative activity compared to CDDP or 14a against the tested cancer lines, with IC 50 values ranging from 1.19 to 3.15 μM, respectively.…”

“…In accordance with our and others' reports, CDDP was not detected via HPLC. 32,37 However, the signals of CDDP (m/z 299.0250) and hydrolyzed CDDP (m/z 264.1563) were recorded via HR-MS (Figure S4H). Considering the acid condition of the tumor microenvironment, physiological condition, and biological medium, the stability of 16a in PBS (pH = 5.5 or 7.4) or DMEM (containing 10% fetal bovine serum) was measured.…”

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 ).…”