Targeted co-delivery of the aldose reductase inhibitor epalrestat and chemotherapeutic doxorubicin <i>via</i> a redox-sensitive prodrug approach promotes synergistic tumor suppression

Banala, Venkatesh Teja; Urandur, Sandeep; Sharma, Shweta; Sharma, Madhu; Shukla, Rahul; Marwaha, Disha; Gautam, Shalini; Dwivedi, Anil Kumar; Mishra, Prabhat Ranjan

doi:10.1039/c9bm00221a

Cited by 37 publications

(13 citation statements)

References 44 publications

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“…Moreover, our study showed that the IC 50 values of ZP and EP on TNBC cell lines (BT549 and Hs578T) were almost equal to another report on the cytotoxic effect of EP on MDA-MB-231. The weak cytotoxic effect of EP is a result of slightly hydrophilic properties and a short half-life, leading to its unsuitability for use as an anticancer drug [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Currently, Epalrestat is the only AKR1B1 inhibitor (ARI) that has been approved by the FDA and is used for metastatic TNBC in phase II clinical trials [ 18 ]. However, its cytotoxic effect is restricted (IC 50 value of 28.83 μg/mL on MDA-MB-231) due to its short half-life and poor hydrophilic nature [ 19 ]. Moreover, its adverse effects remain a vital problem [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Trans-(±)-Kusunokinin Binding to AKR1B1 Inhibits Oxidative Stress and Proteins Involved in Migration in Aggressive Breast Cancer

et al. 2022

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Synthetic trans-()-kusunokinin (()KU), a potential anticancer substance, was revealed to have an inhibitory effect on breast cancer. According to the computational modeling prediction, AKR1B1, an oxidative stress and cancer migration protein, could be a target protein of trans-()-kusunokinin. In this study, we determined the binding of ()KU and AKR1B1 on triple-negative breast and non-serous ovarian cancers. We found that ()KU exhibited a cytotoxic effect that was significantly stronger than zopolrestat (ZP) and epalrestat (EP) (known AKR1B1 inhibitors) on breast and ovarian cancer cells. ()KU inhibited aldose reductase activity that was stronger than trans-()-arctiin (()AR) but weaker than ZP and EP. Interestingly, ()KU stabilized AKR1B1 on SKOV3 and Hs578T cells after being heated at 60 and 75 °C, respectively. ()KU decreased malondialdehyde (MDA), an oxidative stress marker, on Hs578T cells in a dose-dependent manner and the suppression was stronger than EP. Furthermore, ()KU downregulated AKR1B1 and its downstream proteins, including PKC-δ, NF-κB, AKT, Nrf2, COX2, Twist2 and N-cadherin and up-regulated E-cadherin. ()KU showed an inhibitory effect on AKR1B1 and its downstream proteins, similar to siRNA–AKR1B1. Interestingly, the combination of siRNA–AKR1B1 with EP or ()KU showed a greater effect on the suppression of AKR1B1, N-cadherin, E-cadherin and NF-κB than single treatments. Taken together, we concluded that ()KU-bound AKR1B1 leads to the attenuation of cellular oxidative stress, as well as the aggressiveness of breast cancer cell migration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Trans-(±)-Kusunokinin Binding to AKR1B1 Inhibits Oxidative Stress and Proteins Involved in Migration in Aggressive Breast Cancer

et al. 2022

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“…To enhance the stability and avoid the premature delivery of drugs, hydrophobic drugs covalently attached to the polymer has been explored. Epalrestat and DOX were co-delivered at tumor targeted site using redox-sensitive polymer micelles composed of tocopherol polyethylene glycol succinate conjugated with vitamin B6 which acts as cancer targeted moiety [ 281 ]. Synthesized prodrug micelles disrupt in redox tumor environment of MDA MB 231 and 4T1 cell lines, and release both drugs in ratiometric manner.…”

Section: Stimuli Responsive Intelligent Nanomaterials In Cancer Thera...mentioning

confidence: 99%

Smart nanomaterials for cancer diagnosis and treatment

et al. 2022

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Innovations in nanomedicine has guided the improved outcomes for cancer diagnosis and therapy. However, frequent use of nanomaterials remains challenging due to specific limitations like non-targeted distribution causing low signal-to-noise ratio for diagnostics, complex fabrication, reduced-biocompatibility, decreased photostability, and systemic toxicity of nanomaterials within the body. Thus, better nanomaterial-systems with controlled physicochemical and biological properties, form the need of the hour. In this context, smart nanomaterials serve as promising solution, as they can be activated under specific exogenous or endogenous stimuli such as pH, temperature, enzymes, or a particular biological molecule. The properties of smart nanomaterials make them ideal candidates for various applications like biosensors, controlled drug release, and treatment of various diseases. Recently, smart nanomaterial-based cancer theranostic approaches have been developed, and they are displaying better selectivity and sensitivity with reduced side-effects in comparison to conventional methods. In cancer therapy, the smart nanomaterials-system only activates in response to tumor microenvironment (TME) and remains in deactivated state in normal cells, which further reduces the side-effects and systemic toxicities. Thus, the present review aims to describe the stimulus-based classification of smart nanomaterials, tumor microenvironment-responsive behaviour, and their up-to-date applications in cancer theranostics. Besides, present review addresses the development of various smart nanomaterials and their advantages for diagnosing and treating cancer. Here, we also discuss about the drug targeting and sustained drug release from nanocarriers, and different types of nanomaterials which have been engineered for this intent. Additionally, the present challenges and prospects of nanomaterials in effective cancer diagnosis and therapeutics have been discussed.

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“…In this regard, co‐delivery of DOX and Fidarestat has been shown to lower the MDR1, MRP1 and ABCG2 drug transporters, thereby reducing the drug efflux in tumour cells and decreasing the drug resistance 100 . Furthermore, a prodrug nano assembly of Epalrestat and DOX has increased the uptake of DOX and synergically inhibited the cell growth and improved apoptosis 101 …”

Section: Biomarker For Predictionmentioning

confidence: 99%

Role of aldo‐keto reductase family 1 member B1 (AKR1B1) in the cancer process and its therapeutic potential

Khayami

Hashemi

Kerachian

2020

J Cellular Molecular Medi

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The role of aldo‐keto reductase family 1 member B1 (AKR1B1) in cancer is not totally clear but growing evidence is suggesting to have a great impact on cancer progression. AKR1B1 could participate in a complicated network of signalling pathways, proteins and miRNAs such as mir‐21 mediating mechanisms like inflammatory responses, cell cycle, epithelial to mesenchymal transition, cell survival and apoptosis. AKR1B1 has been shown to be mostly overexpressed in cancer. This overexpression has been associated with inflammatory mediators including nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB), cell cycle mediators such as cyclins and cyclin‐dependent kinases (CDKs), survival proteins and pathways like mammalian target of rapamycin (mTOR) and protein kinase B (PKB) or AKT, and other regulatory factors in response to reactive oxygen species (ROS) and prostaglandin synthesis. In addition, inhibition of AKR1B1 has been shown to mostly have anti‐cancer effects. Several studies have also suggested that AKR1B1 inhibition as an adjuvant therapy could render tumour cells more sensitive to anti‐cancer therapy or alleviate the adverse effects of therapy. AKR1B1 could also be considered as a potential cancer diagnostic biomarker since its promoter has shown high levels of methylation. Although pre‐clinical investigations on the role of AKR1B1 in cancer and the application of its inhibitors have shown promising results, the lack of clinical studies on AKR1B1 inhibitors has hampered the use of these drugs to treat cancer. Thus, there is a need to conduct more clinical studies on the application of AKR1B1 inhibitors as adjuvant therapy on different cancers.

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Targeted co-delivery of the aldose reductase inhibitor epalrestat and chemotherapeutic doxorubicin via a redox-sensitive prodrug approach promotes synergistic tumor suppression

Abstract: Redox responsive epalrestat prodrug micelles facilitate synergistic concentrations of doxorubicin with an advantage of CD44 down-regulation and reduced cardiotoxicity.

Cited by 37 publications

References 44 publications

Trans-(±)-Kusunokinin Binding to AKR1B1 Inhibits Oxidative Stress and Proteins Involved in Migration in Aggressive Breast Cancer

Trans-(±)-Kusunokinin Binding to AKR1B1 Inhibits Oxidative Stress and Proteins Involved in Migration in Aggressive Breast Cancer

Smart nanomaterials for cancer diagnosis and treatment

Role of aldo‐keto reductase family 1 member B1 (AKR1B1) in the cancer process and its therapeutic potential

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