Adapalene synergistically with doxorubicin promotes apoptosis of TNBC Cells by hyperactivation of the ERK1/2 pathway through ROS induction

Mehraj, Umar; Mir, Irfan Ahmad; Hassan, Mahboob ul; Mir, Nissar Ahmad; Mir, Manzoor Ahmad

doi:10.21203/rs.3.rs-1590566/v1

Cited by 5 publications

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“…MDA-MB-231 was treated with GDC, ADA, or both for 24 and 48 h. All the cells were collected, including free-floating and adherent cells, and stained with the fluorescent dyes FITC-Annexin V and 7-AAD as recommended by the manufacturer. Flow cytometry was performed at the Department of Biotechnology, National Institute of Technology, Rourkela, Odisha, India, on a BD Accuri™ C6 flow cytometer ( Mehraj et al, 2022b ).…”

Section: Methodsmentioning

confidence: 99%

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Adapalene inhibits the growth of triple-negative breast cancer cells by S-phase arrest and potentiates the antitumor efficacy of GDC-0941

et al. 2022

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Although advances in diagnostics and therapeutics have prolonged the survival of triple-negative breast cancer (TNBC) patients, metastasis, therapeutic resistance, and lack of targeted therapies remain the foremost hurdle in the effective management of TNBC. Thus, evaluation of new therapeutic agents and their efficacy in combination therapy is urgently needed. The third-generation retinoid adapalene (ADA) has potent antitumor activity, and using ADA in combination with existing therapeutic regimens may improve the effectiveness and minimize the toxicities and drug resistance. The current study aimed to assess the anticancer efficacy of adapalene as a combination regimen with the PI3K inhibitor (GDC-0941) in TNBC in vitro models. The Chou–Talalay’s method evaluated the pharmacodynamic interactions (synergism, antagonism, or additivity) of binary drug combinations. Flow cytometry, Western blotting, and in silico studies were used to analyze the mechanism of GDC–ADA synergistic interactions in TNBC cells. The combination of GDC and ADA demonstrated a synergistic effect in inhibiting proliferation, migration, and colony formation of tumor cells. Accumulation of reactive oxygen species upon co-treatment with GDC and ADA promoted apoptosis and enhanced sensitivity to GDC in TNBC cells. The findings indicate that ADA is a promising therapeutic agent in treating advanced BC tumors and enhance sensitivity to GDC in inhibiting tumor growth in TNBC models while reducing therapeutic resistance.

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Section: Methodsmentioning

confidence: 99%

“…The cells were filtered prior to flow cytometry, using a 70-m cell strainer. Flow cytometry was performed at the NIT Rourkela, India ( Mehraj et al, 2022b ).…”

Section: Methodsmentioning

confidence: 99%

Adapalene inhibits the growth of triple-negative breast cancer cells by S-phase arrest and potentiates the antitumor efficacy of GDC-0941

et al. 2022

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“…MDA-MB-231 was treated with acetate extract for 24 and 48 h. As instructed by the manufacturer, adherent and free-floating cells were all collected and stained with the fluorescent dyes FITC-Annexin V and PI. Flow cytometry was performed at the Department of Biotechnology, National Institute of Technology, Rourkela, Odisha, India, on a BD Accuri ™ C6 flow cytometer (Mehraj et al, 2022)…”

Section: Annexin V/pi Apoptosis Detectionmentioning

confidence: 99%

Network pharmacology combined with molecular docking and in vitro verification reveals the therapeutic potential of Delphinium roylei munz constituents on breast carcinoma

Mir,

Bhat,

Kumar

et al. 2023

Front. Pharmacol.

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Delphinium roylei Munz is an indigenous medicinal plant to India where its activity against cancer has not been previously investigated, and its specific interactions of bioactive compounds with vulnerable breast cancer drug targets remain largely unknown. Therefore, in the current study, we aimed to evaluate the anti-breast cancer activity of different extracts of D. roylei against breast cancer and deciphering the molecular mechanism by Network Pharmacology combined with Molecular Docking and in vitro verification. The experimental plant was extracted with various organic solvents according to their polarity index. Phytocompounds were identified by High resolution-liquid chromatography-mass spectrometry (HR-LC/MS) technique, and SwissADME programme evaluated their physicochemical properties. Next, target(s) associated with the obtained bioactives or breast cancer-related targets were retrieved by public databases, and the Venn diagram selected the overlapping targets. The networks between overlapping targets and bioactive were visualized, constructed, and analyzed by STRING programme and Cytoscape software. Finally, we implemented a molecular docking test (MDT) using AutoDock Vina to explore key target(s) and compound(s). HR-LC/MS detected hundreds of phytocompounds, and few were accepted by Lipinski’s rules after virtual screening and therefore classified as drug-like compounds (DLCs). A total of 464 potential target genes were attained for the nine quantitative phytocompounds and using Gene Cards, OMIM and DisGeNET platforms, 12063 disease targets linked to breast cancer were retrieved. With Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment, a total of 20 signalling pathways were manifested, and a hub signalling pathway (PI3K-Akt signalling pathway), a key target (Akt1), and a key compound (8-Hydroxycoumarin) were selected among the 20 signalling pathways via molecular docking studies. The molecular docking investigation revealed that among the nine phytoconstituents, 8-hydroxycoumarin showed the best binding energy (−9.2 kcal/mol) with the Akt1 breast cancer target. 8-hydroxycoumarin followed all the ADME property prediction using SwissADME, and 100 nanoseconds (ns) MD simulations of 8-hydroxycoumarin complexes with Akt1 were found to be stable. Furthermore, D. roylei extracts also showed significant antioxidant and anticancer activity through in vitro studies. Our findings indicated for the first time that D. roylei extracts could be used in the treatment of BC.

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“…In addition to its use in the treatment of dermatological conditions, it has been reported that ADP can potentially target various cancer cell types, including cervical cancer and cervical intraepithelial neoplasia, ovarian cancer, bladder cancer, prostate cancer, and breast cancer ( DiSilvestro et al, 2001 ; Ghosalkar et al, 2018 ; Rusu et al, 2020 ; Mehraj et al, 2022b ). ADP potentially exhibits its effect by regulating the extracellular signal-regulated protein kinase (ERK1/2) and glutamic-oxaloacetic transaminase 1 (GOT1), thereby causing S-phase arrest, DNA damage, colony formation and migration inhibition, ROS induction, and caspase-mediated apoptosis to ultimately suppress tumor growth ( Wang et al, 2019 ; Mehraj et al, 2022a ). However, studies to decipher the exact mechanistic procedures involved in its antineoplastic action are currently underway.…”

Section: Introductionmentioning

confidence: 99%

Development of mucoadhesive adapalene gel for biotherapeutic delivery to vaginal tissue

Afzaal

Shahiq-uz-Zaman²,

Saeed³

et al. 2022

Front. Pharmacol.

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Purpose: Alternate formulation strategies need to be devised for improving the absorption and bioavailability of drug molecules administered through the intravaginal route. Enhancing the coating of vaginal mucosa can aid the achievement of this goal. The aim of the current study is to develop a mucoadhesive formulation having adequate adhesiveness, spreading, and viscosity profiles that can ensure good tissue absorption of adapalene upon intravaginal application.Method: A combination of mucoadhesive agents has been employed, including Carbopol-934, HPMC K-15M, and xanthan gum, in varying ratios to formulate five different gels. Furthermore, a cost-effective UV-spectroscopic analytical method was developed to quantify the amount of adapalene in tested samples, both of in vitro and in vivo origin. The analytical method was validated for different parameters, including specificity, linearity, range, accuracy, precision, and ruggedness. The modified USP-II apparatus was used for dissolution studies, while in vivo pharmacokinetic validation was performed in a murine model.Result: Of all the tested formulations, on the basis of the rheo-mechanical attributes, ACX3 performed better than the rest, including the commercially available intravaginal reference product. ACX3 had an average adhesion time of 12 min and a spread diameter of 37 mm. It showed 35 mm as average distance travelled by the diluted sample for leakage assessment. The analytical method developed for the adapalene muco-adhesive gel was within the range for all the validation parameters. For further evaluating the performance of the formulation, dissolution studies were conducted in simulated vaginal conditions which showed 94.83% of drug release within 5 minutes, while on completion of 30 min, it was measured to be 92.90%. Moreover, approximately 67% of the administered drug was recovered after 5 min of administration as evaluated through tissue recovery procedures in mice.Conclusion: The study aided in development of a formulation which can enhance the muco-adhesion of the drug molecule, resulting in an improved pharmacokinetic profile. Moreover, it established an efficient assay method which can be employed for in vitro and in vivo quantification of adapalene in simulated and physiological fluids.

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Adapalene synergistically with doxorubicin promotes apoptosis of TNBC Cells by hyperactivation of the ERK1/2 pathway through ROS induction

Cited by 5 publications

References 0 publications

Adapalene inhibits the growth of triple-negative breast cancer cells by S-phase arrest and potentiates the antitumor efficacy of GDC-0941

Adapalene inhibits the growth of triple-negative breast cancer cells by S-phase arrest and potentiates the antitumor efficacy of GDC-0941

Network pharmacology combined with molecular docking and in vitro verification reveals the therapeutic potential of Delphinium roylei munz constituents on breast carcinoma

Development of mucoadhesive adapalene gel for biotherapeutic delivery to vaginal tissue

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