Antitumor and toxicity study of mitochondria-targeted triptolide derivatives using triphenylphosphine (TPP+) as a carrier

Song, Huina; Xing, Wenlan; Shi, Xiaojia; Zhang, Tao; Lou, Hongxiang; Fan, Peihong

doi:10.1016/j.bmc.2021.116466

Cited by 14 publications

(16 citation statements)

References 32 publications

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“…The triphenylphosphonium-based modification of drugs to facilitate mitochondrial targeting is not a novel idea, as there is a wealth of literature on the good biological effects of small molecules containing TPP [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. The hydroxy and carboxyl groups of natural products are some activating groups that are often used to link pharmacophores such as TPP [ 6 , 7 , 8 ]. α -Mangostin containing phenolic hydroxy groups was isolated from the fruit hull of Garcinia mangostana in our previous study.…”

Section: Discussionmentioning

confidence: 99%

“…The difference in electric potential between the two membranes is called mitochondrial membrane potential (Δψ m ), which is much higher in tumor cells than that in normal cells [ 3 ]. Therefore, using this feature, some positively charged drug molecules or agents such as rhodamine 123, dequalinium, guanidinium, and triphenylphosphonium (TPP) cations can be driven by Δψ m to accumulate in mitochondria and achieve targeted antitumor effects able to destroy cancer cells [ 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Natural plant polyphenols such as resveratrol, quercetin, and curcumin, continue to be the subject of extensive investigations due to their promising anticancer properties and relatively low toxicity. Thus, hydroxy or carboxyl groups in these bioactive natural products can be linked with mitochondrion-targeted TPP to improve antitumor activities [ 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone

et al. 2023

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α-Mangostin, a natural xanthone, was found to have anticancer effects, but these effects are not sufficient to be effective. To increase anticancer potential and selectivity, a triphenylphosphonium cation moiety (TPP) was introduced to α-mangostin to specifically target cancer cell mitochondria. Compared to the parent compound, the cytotoxicity of the synthesized compound 1b increased by one order of magnitude. Mechanistic analysis revealed that the anti-tumor effects were involved in the mitochondrial apoptotic pathway by prompting apoptosis and arresting the cell cycle at the G0/G1 phase, increasing the production of reactive oxygen species (ROS), and reducing mitochondrial membrane potential (Δψm). More notably, the antitumor activity of compound 1b was further confirmed by zebrafish models, which remarkably inhibited cancer cell proliferation and migration, as well as zebrafish angiogenesis. Taken together, our results for the first time indicated that TPP-linked 1b could lead to the development of new mitochondrion-targeting antitumor agents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone

et al. 2023

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“…For example, the distinguishing feature of lipophilic cations is that their positive charge is delocalized over a large and hydrophobic surface area that can easily pass through the phospholipid bilayer [ 23 ], enabling them to accumulate into the mitochondrial matrix in response to membrane potential [ 24 , 25 , 26 ]. However, the inherent toxicity associated with lipophilic cations has hindered their clinical development, and thus, has limited applications [ 27 , 28 ]. Synthetic peptides by altering lipophilicity and charge composition can also act as mitochondria-targeting carriers, which exhibit strong affinity for mitochondria.…”

Section: Introductionmentioning

confidence: 99%

A Cationic Amphiphilic AIE Polymer for Mitochondrial Targeting and Imaging

Zhou

Wang

et al. 2022

Pharmaceutics

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Mitochondria are important organelles that play key roles in generating the energy needed for life and in pathways such as apoptosis. Direct targeting of antitumor drugs, such as doxorubicin (DOX), to mitochondria into cells is an effective approach for cancer therapy and inducing cancer cell death. To achieve targeted and effective delivery of antitumor drugs to tumor cells, to enhance the therapeutic effect, and to reduce the side effects during the treatment, we prepared a cationic amphiphilic polymer with aggregation-induced emission (AIE) characteristic. The polymer could be localized to mitochondria with excellent organelle targeting, and it showed good mitochondrial targeting with low toxicity. The polymer could also self-assemble into doxorubicin-loaded micelles in phosphate buffer, with a particle size of about 4.3 nm, an encapsulation rate of 11.03%, and micelle drug loading that reached 0.49%. The results of in vitro cytotoxicity experiments showed that the optimal dosage was 2.0 μg/mL, which had better inhibitory effect on tumor cells and less biological toxicity on heathy cells. Therefore, the cationic amphiphilic polymer can partially replace expensive commercial mitochondrial targeting reagents, and it can be also used as a drug loading tool to directly target mitochondria in cells for corresponding therapeutic research.

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“…Mitochondria are small subcellular organelles that generate most cellular energy in the form of adenosine triphosphate (ATP) and are indispensable for a wide range of cellular processes. − Mitochondrial defects or dysfunctions are therefore involved in a plethora of diseases, especially in cancer. − Consequently, there has been considerable interest in delivering anticancer drugs specifically into mitochondria to rectify mitochondrial defects or dysfunctions. − To enhance the exposure of anticancer drugs in mitochondria, they are often selectively delivered inside the mitochondria by linking to mitochondria vectors, which are membrane permeable and could drive the selective accumulation of the attached drugs within the mitochondria in cells and in vivo . , …”

Section: Introductionmentioning

confidence: 99%

A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities

et al. 2022

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Phenylbutyric acid (PBA) has been reported as a dual inhibitor of pyruvate dehydrogenase kinases (PDKs) and histone deacetylases (HDACs), exhibiting anticancer effects. However, the low membrane permeability and poor cellular uptake limit its access to the target organelle, resulting in weak potencies against the intended targets. Herein, we report the design and identification of a novel 4-CF3-phenyl triphenylphosphonium-based PBA conjugate (53) with improved in vitro and in vivo anticancer activities. Compound 53 exhibited an IC50 value of 2.22 μM against A375 cells, outperforming the parent drug PBA by about 4000-fold. In the A375 cell-derived xenograft mouse model, 53 reduced the tumor growth by 76% at a dose of 40 mg/kg, while PBA only reduced the tumor growth by 10% at a dose of 80 mg/kg. On the basis of these results, 53 may be considered for further preclinical evaluations for cancer therapy.

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Antitumor and toxicity study of mitochondria-targeted triptolide derivatives using triphenylphosphine (TPP+) as a carrier

Cited by 14 publications

References 32 publications

Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone

Design, Synthesis, Biological Evaluation, and Preliminary Mechanistic Study of a Novel Mitochondrial-Targeted Xanthone

A Cationic Amphiphilic AIE Polymer for Mitochondrial Targeting and Imaging

A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities

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