Novel Platinum(IV) complexes intervene oxaliplatin resistance in colon cancer via inducing ferroptosis and apoptosis

Self Cite

Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking platinum(II) agents and glycyrrhetinic acid (GA) were designed and synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including cisplatin resistance cells than cisplatin and simultaneously displayed good liver-targeting ability. Moreover, complex 20 can significantly cause DNA damage and mitochondrial dysfunction, promote reactive oxygen species generation, activate endoplasmic reticulum stress, and eventually induce apoptosis. Additionally, complex 20 can effectively inhibit cell migration and invasion and trigger autophagy and ferroptosis in HepG-2 cells. More importantly, complex 20 demonstrated stronger tumor inhibition ability than cisplatin or the combo of cisplatin/GA with almost no systemic toxicity in HepG-2 or A549 xenograft models. Collectively, complex 20 could be developed as a potential anti-HCC agent for cancer treatment.

Section: Resultsmentioning

confidence: 99%

“…The biological assay procedures were performed according to previous work, ,, and the detailed methods are described in the Supporting Information (Part 1).…”

Section: Methodsmentioning

confidence: 99%

Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance

Huang,

Li,

et al. 2024

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“…The biological assays were performed as described previously, ,,, and the detailed methods are described in the Supporting Information (Part 1).…”

Section: Methodsmentioning

confidence: 99%

Novel NF-κB Inhibitor-Conjugated Pt(IV) Prodrug to Enable Cancer Therapy through ROS/ER Stress and Mitochondrial Dysfunction and Overcome Multidrug Resistance

Wang,

Li,

Jiang

et al. 2024

Self Cite

Although cisplatin has been widely used for clinical purposes, its application is limited due to its obvious side effects. To mitigate the defects of cisplatin, here, six "multitarget prodrugs" were synthesized by linking cisplatin and NF-κB inhibitors. Notably, complex 9 demonstrated a 63-fold enhancement in the activity against A549/CDDP cells with lower toxicity toward normal LO2 cells compared to cisplatin. Additionally, complex 9 could effectively cause DNA damage, induce mitochondrial dysfunction, generate reactive oxygen species, and induce cell apoptosis through the mitochondrial pathway and ER stress. Remarkably, complex 9 effectively inhibited the NF-κB/MAPK signaling pathway and disrupted the PI3K/AKT signaling transduction. Importantly, complex 9 showed superior in vivo antitumor efficiency compared to cisplatin or the combination of cisplatin/4, without obvious systemic toxicity in A549 or A549/ CDDP xenograft models. Our results demonstrated that the dual-acting mechanism endowed the complexes with high efficiency and low toxicity, which may represent an efficient strategy for cancer therapy.

“…18−21 For the Pt(IV)-prodrug approach, Wang's group very recently reported a series of ligustrazine-derived oxaliplatin Pt(IV)-prodrug complexes, in which the release of ligustrazine from the prodrug as a ferroptosis inducer could significantly enhance the efficacy of oxaliplatin in HCT-116/ OXA cells and in the corresponding xenograft model. 22 More prodrug examples have been published by Kowol's group and are also designed based on oxaliplatin. L-buthionine-S,Rsulfoximine (BSO), as a glutamate-cysteine ligase inhibitor on the axial position (BSO-OxR, Figure 1), enables the Pt(IV)prodrug to significantly enhance the in vivo efficacy in oxaliplatin-resistant CT26-bearing allograft mice.…”

Section: ■ Introductionmentioning

confidence: 99%

“… Similar results have been published by Lu and Cao’s group in recent years using a combination of oxaliplatin with KLF5 and STAT3 inhibitors, respectively, to effectively restore the antitumor activity of oxaliplatin in resistant CRC cell lines. , Both STAT3 and KLF5 are involved mainly in tumor cell functions to control cell proliferation, migration, and apoptosis. On the other hand, in order to fundamentally solve the problem of tumor resistance to oxaliplatin, medicinal chemists have designed and synthesized a large number of new Pt(II) derivatives, including Pt(IV) prodrugs in an attempt to discover a new generation of platinum-based anticancer agents. − For the Pt(IV)-prodrug approach, Wang’s group very recently reported a series of ligustrazine-derived oxaliplatin Pt(IV)-prodrug complexes, in which the release of ligustrazine from the prodrug as a ferroptosis inducer could significantly enhance the efficacy of oxaliplatin in HCT-116/OXA cells and in the corresponding xenograft model . More prodrug examples have been published by Kowol’s group and are also designed based on oxaliplatin.…”

Section: Introductionmentioning

confidence: 99%

Discovery of the Next-Generation Platinum-Based Anticancer Agents for Combating Oxaliplatin-Induced Drug Resistance

Sun,

Han,

et al. 2024

Oxaliplatin-based chemotherapy has proven to be one of the most effective treatments for advanced or metastatic colorectal cancer. However, increasing clinical resistance to oxaliplatin poses unprecedented challenges for both patients and clinicians. Despite extensive efforts to combat this issue, to date, no new molecules have been discovered that can successfully replace oxaliplatin. With the aim of developing a new generation of Pt(II)-based anticancer agents in response to the challenges of oxaliplatin-induced drug resistance, we performed a systematic screening of new Pt(II)-complexes with a quantitative structure− activity relationship (QSAR) study based on their antiresistance activity against oxaliplatin-resistant colon cancer cells. The results revealed that both the structure and chirality of the chelating ligand had a significant impact on the antiresistance properties of the Pt(II)-complexes. Our study culminated in the identification of chiral R-binaphthyldiamine-ligated Pt(II)-malonatoglycoconjugates that can completely counteract oxaliplatin resistance with excellent in vitro and in vivo potency.