Utilization of redox modulating small molecules that selectively act as pro-oxidants in cancer cells to open a therapeutic window for improving cancer therapy

A critical hallmark of cancer cells is their ability to evade programmed apoptotic cell death. Consequently, resistance to anti-cancer therapeutics is a hurdle often observed in the clinic. Ferroptosis, a non-apoptotic form of cell death distinguished by toxic lipid peroxidation and iron accumulation, has garnered substantial attention as an alternative therapeutic strategy to selectively destroy tumours. Although there is a plethora of research outlining the molecular mechanisms of ferroptosis, these findings are yet to be translated into clinical compounds inducing ferroptosis. In this perspective, we elaborate on how ferroptosis can be leveraged in the clinic. We discuss a therapeutic window for compounds inducing ferroptosis, the subset of tumour types that are most sensitive to ferroptosis, conventional therapeutics that induce ferroptosis, and potential strategies for lowering the threshold for ferroptosis.

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Hyaluronan based Multifunctional Nano-carriers for Combination Cancer Therapy

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200922113846 ◽

2020 ◽

Vol 20 ◽

Author(s):

Menghan Gao ◽

Hong Deng ◽

Weiqi Zhang

Keyword(s):

Cancer Therapy ◽

Combination Therapy ◽

Cancer Cells ◽

Drug Loading ◽

Tumor Therapy ◽

Drug Carriers ◽

Functional Sites ◽

Therapeutic Modalities ◽

Combination Cancer Therapy ◽

Targeting Strategy

: Hyaluronan (HA) is a natural linear polysaccharide that has excellent hydrophilicity, biocompatibility, biodegradability, and low immunogenicity, making it one of the most attractive biopolymers used for biomedical researches and applications. Due to the multiple functional sites on HA and its intrinsic affinity for CD44, a receptor highly expressed on various cancer cells, HA has been widely engineered to construct different drug-loading nanoparticles (NPs) for CD44- targeted anti-tumor therapy. When a cocktail of drugs is co-loaded in HA NP, a multifunctional nano-carriers could be obtained, which features as a highly effective and self-targeting strategy to combat the cancers with CD44 overexpression. The HA-based multidrug nano-carriers can be a combination of different drugs, various therapeutic modalities, or the integration of therapy and diagnostics (theranostics). Up to now, there are many types of HA-based multidrug nano-carriers constructed by different formulation strategies including drug co-conjugates, micelles, nano-gels and hybrid NP of HA and so on. This multidrug nano-carrier takes the full advantages of HA as NP matrix, drug carriers and targeting ligand, representing a simplified and biocompatible platform to realize the targeted and synergistic combination therapy against the cancers. In this review, recent progresses about HA-based multidrug nano-carriers for combination cancer therapy are summarized and its potential challenges for translational applications have been discussed.

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An artificial cell system for biocompatible gene delivery in cancer therapy

Nanoscale ◽

10.1039/c9nr09131a ◽

2020 ◽

Vol 12 (18) ◽

pp. 10189-10195 ◽

Cited By ~ 7

Author(s):

Xin Zhao ◽

Dongyang Tang ◽

Ying Wu ◽

Shaoqing Chen ◽

Cheng Wang

Keyword(s):

Gene Therapy ◽

Cancer Therapy ◽

Gene Delivery ◽

Cancer Cells ◽

Cell System ◽

Artificial Cell

The artifical cell system for the gene therapy of cancer might be a promising approach for the reversal of neoplastic progress of cancer cells.

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Nuclear Transglutaminase 2 interacts with topoisomerase II⍺ to promote DNA damage repair in lung cancer cells

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02009-2 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xiao Lei ◽

Kun Cao ◽

Yuanyuan Chen ◽

Hui Shen ◽

Zhe Liu ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Cancer Therapy ◽

Cancer Cells ◽

Protein Localization ◽

Transglutaminase 2 ◽

Lung Cancer Cells ◽

Mass Spectrometry Analysis ◽

Cancer Resistance ◽

Dsb Repair

Abstract Background To block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death. DSB repair depends on a sequential activation of DNA repair factors that may be potentially targeted for clinical cancer therapy. Up to now, many protein components of DSB repair complex remain unclear or poorly characterized. In this study, we discovered that Transglutaminase 2 (TG2) acted as a new component of DSB repair complex. Methods A bioinformatic analysis was performed to identify DNA damage relative genes from dataset from The Cancer Genome Atlas. Immunofluorescence and confocal microscopy were used to monitor the protein localization and recruitment kinetics. Furthermore, immunoprecipitation and mass spectrometry analysis were performed to determine protein interaction of both full-length and fragments or mutants in distinct domain. In situ lung cancer model was used to study the effects cancer therapy in vivo. Results After DSB induction, cytoplasmic TG2 was extensively mobilized and translocated into nucleus after phosphorylated at T162 site by DNA-PKcs. Nuclear TG2 quickly accumulated at DSB sites and directly interacting with Topoisomerase IIα (TOPOIIα) with its TGase domain to promote DSB repair. TG2 deficient cells lost capacity of DSB repair and become susceptible to ionizing radiation. Specific inhibition of TG2-TOPOIIα interaction by glucosamine also significantly inhibited DSB repair, which increased sensitivity in lung cancer cells and engrafted lung cancers. Conclusions These findings elucidate new mechanism of TG2 in DSB repair trough directly interacting with TOPOIIα, inhibition of which provided potential target for overcoming cancer resistance.

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Magneto Mitochondrial Dysfunction Mediated Cancer Cell Death Using Intracellular Magnetic Nano-Transducers

Biomaterials Science ◽

10.1039/d1bm00419k ◽

2021 ◽

Author(s):

Wooram Park ◽

Seok-Jo Kim ◽

Paul Cheresh ◽

Jeanho Yun ◽

Byeongdu Lee ◽

...

Keyword(s):

Cell Death ◽

Cancer Therapy ◽

Mitochondrial Dysfunction ◽

Cancer Cells ◽

Cancer Cell ◽

High Sensitivity ◽

Intrinsic Pathway ◽

Cancer Cell Death

Mitochondria are crucial regulators of the intrinsic pathway of cancer cell death. The high sensitivity of cancer cells to mitochondrial dysfunction offers opportunities for emerging targets in cancer therapy. Herein,...

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Drug Discovery Targeting Focal Adhesion Kinase (FAK) as a Promising Cancer Therapy

Molecules ◽

10.3390/molecules26144250 ◽

2021 ◽

Vol 26 (14) ◽

pp. 4250

Author(s):

Xiao-Jing Pang ◽

Xiu-Juan Liu ◽

Yuan Liu ◽

Wen-Bo Liu ◽

Yin-Ru Li ◽

...

Keyword(s):

Cancer Therapy ◽

Phase I ◽

Small Molecules ◽

Anticancer Agents ◽

Biological Function ◽

Human Cancer ◽

Tumor Cell Growth ◽

Research Groups ◽

Human Cancer Cell Lines ◽

Opening Up

FAK is a nonreceptor intracellular tyrosine kinase which plays an important biological function. Many studies have found that FAK is overexpressed in many human cancer cell lines, which promotes tumor cell growth by controlling cell adhesion, migration, proliferation, and survival. Therefore, targeting FAK is considered to be a promising cancer therapy with small molecules. Many FAK inhibitors have been reported as anticancer agents with various mechanisms. Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase I), and BI-853520 (Phase I) are undergoing clinical trials in different phases. Up to now, there have been many novel FAK inhibitors with anticancer activity reported by different research groups. In addition, FAK degraders have been successfully developed through “proteolysis targeting chimera” (PROTAC) technology, opening up a new way for FAK-targeted therapy. In this paper, the structure and biological function of FAK are reviewed, and we summarize the design, chemical types, and activity of FAK inhibitors according to the development of FAK drugs, which provided the reference for the discovery of new anticancer agents.

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Bioinformatic Analysis of the Nicotinamide Binding Site in Poly(ADP-Ribose) Polymerase Family Proteins

Cancers ◽

10.3390/cancers13061201 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1201

Author(s):

Garri Manasaryan ◽

Dmitry Suplatov ◽

Sergey Pushkarev ◽

Viktor Drobot ◽

Alexander Kuimov ◽

...

Keyword(s):

Molecular Modeling ◽

Cancer Therapy ◽

Adverse Effects ◽

Binding Site ◽

Cancer Cells ◽

Anticancer Drugs ◽

Bioinformatic Analysis ◽

Parp Inhibitors ◽

Functional Region ◽

D Loop

The PARP family consists of 17 members with diverse functions, including those related to cancer cells’ viability. Several PARP inhibitors are of great interest as innovative anticancer drugs, but they have low selectivity towards distinct PARP family members and exert serious adverse effects. We describe a family-wide study of the nicotinamide (NA) binding site, an important functional region in the PARP structure, using comparative bioinformatic analysis and molecular modeling. Mutations in the NA site and D-loop mobility around the NA site were identified as factors that can guide the design of selective PARP inhibitors. Our findings are of particular importance for the development of novel tankyrase (PARPs 5a and 5b) inhibitors for cancer therapy.

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Biocompatible hole scavenger–assisted graphene oxide dots for photodynamic cancer therapy

Nanoscale ◽

10.1039/d1nr01476e ◽

2021 ◽

Author(s):

Chun-Yan Shih ◽

Wei-Lun Huang ◽

I-Ting Chiang ◽

Wu-Chou Su ◽

Hsisheng Teng

Keyword(s):

Ascorbic Acid ◽

Graphene Oxide ◽

Cancer Therapy ◽

Cancer Cells ◽

Nitrogen Doped ◽

Photodynamic Cancer Therapy ◽

Hole Scavenger ◽

Nitrogen Doped Graphene ◽

Doped Graphene

Tuning of the nitrogen-doped graphene oxide dot and ascorbic acid concentrations can selectively kill cancer cells through either apoptosis or necrosis.

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