6 results on '"Prasad, N."'
Search Results
2. Andrographolide reverts multidrug resistance in KBChR 8‐5 cells through AKT signaling pathway.
- Author
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Lakra, Deepa S., Bharathiraja, Pradhapsingh, Dhanalakshmi, T., and Prasad, N. Rajendra
- Subjects
MULTIDRUG resistance ,DRUG resistance in cancer cells ,CELLULAR signal transduction ,ANDROGRAPHIS paniculata ,CANCER cell proliferation ,P-glycoprotein - Abstract
Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. P‐glycoprotein (P‐gp) one of the ATP‐binding cassette (ABC) transporters plays an important role in MDR. In this study, we examined the sensitizing property of andrographolide (Andro) to reverse MDR in the drug‐resistant KBChR 8‐5 cells. Andro exhibited increased cytotoxicity in a concentration‐dependent manner in the P‐gp overexpressing KBChR 8‐5 cells. Furthermore, Andro showed synergistic interactions with PTX and DOX in this drug‐resistant cells. Andro co‐administration enhanced PTX‐ and DOX‐induced cytotoxicity and reduced cell proliferation in the MDR cancer cells. Moreover, reactive oxygen species (ROS) were elevated with a decrease in the mitochondrial membrane potential (MMP) during Andro and chemotherapeutic drugs combination treatment in the drug‐resistant cells. Furthermore, Andro and PTX‐induced cell cycle arrest was observed in the drug‐resistant cell. We also noticed that the expression of ABCB1 and AKT were downregulated during Andro (4 µM) treatment. Furthermore, Andro treatment enhanced the expression of caspase 3 and caspase 9 in the combinational groups that support the enhanced apoptotic cell death in drug‐resistant cancer cells. Therefore, the results reveal that Andro plays a role in the reversal of P‐gp‐mediated MDR in KBChR 8‐5 cells which might be due to regulating ABCB1/AKT signaling pathway. Significance statement: ATP‐binding cassette (ABC) transporters‐mediated multidrug resistance (MDR) is a major hindrance during cancer treatment. Efflux mechanism of P‐glycoprotein (P‐gp) decreases bioavailability and efficacy of chemotherapeutic drugs. Already known inhibitors of P‐gp exhibit higher toxicity to the untargeted cells. Phytochemicals have great potential to reverse the MDR mechanism in cancer cells with less toxicity. Andrographolide (Andro), a phytochemical of Andrographis paniculata, enhanced the efficacy of the chemotherapeutic drugs and reverses drug resistance in MDR cancer cells. Therefore, Andro can be considered as a potent candidate to overcome MDR after preclinical and clinical validations. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. Reversal of P‐glycoprotein‐mediated multidrug resistance by natural N‐alkylated indole alkaloid derivatives in KB‐ChR‐8‐5 drug‐resistant cancer cells.
- Author
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Bharathiraja, Pradhapsingh, Cardoso, David S. P., Rajendra Prasad, N., Mulhovo, Silva, Lakra, Deepa S., and Ferreira, Maria‐José U.
- Subjects
ATP-binding cassette transporters ,INDOLE alkaloids ,P-glycoprotein ,MULTIDRUG resistance ,NF-kappa B ,INDOLE derivatives ,NATURAL immunity - Abstract
Multidrug resistance (MDR) remains a significant challenge in cancer chemotherapy due to the overexpression of ATP‐binding cassette drug‐efflux transporters, namely P‐glycoprotein (P‐gp)/ATP‐binding cassette subfamily B member 1. In this study, derivatives of N‐alkylated monoterpene indole alkaloids such as N‐(para‐bromobenzyl) (NBBT), N‐(para‐methylbenzyl) (NMBT), and N‐(para‐methoxyphenethyl) (NMPT) moieties were investigated for the reversal of P‐gp‐mediated MDR in drug‐resistant KB colchicine‐resistant 8‐5 (KB‐ChR‐8‐5) cells. Among the three indole alkaloid derivatives, the NBBT exhibited the highest P‐gp inhibitory activity in a dose‐dependent manner. Further, it significantly decreased P‐gp overexpression by inactivating the nuclear translocation of the nuclear factor kappa B p‐50 subunit. In the cell survival assay, doxorubicin showed 6.3‐fold resistance (FR) in KB‐ChR‐8‐5 cells compared with its parental KB‐3‐1 cells. However, NBBT significantly reduced doxorubicin FR to 1.7, 1.3, and 0.4 and showed strong synergism with doxorubicin for all the concentrations studied in the drug‐resistant cells. Furthermore, NBBT and doxorubicin combination decreased the cellular migration and showed increased apoptotic incidence by downregulating Bcl‐2, then activating BAX, caspase 3, and p53. The present findings suggest that NBBT could be a lead candidate for the reversal of P‐gp‐ mediated multidrug resistance in cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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4. Natural medicinal compounds target signal transduction pathways to overcome ABC drug efflux transporter-mediated multidrug resistance in cancer.
- Author
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Bharathiraja, Pradhapsingh, Yadav, Priya, Sajid, Andaleeb, Ambudkar, Suresh V., and Prasad, N. Rajendra
- Abstract
ATP-binding cassette (ABC) transporters such as ABCB1, ABCG2, and ABCC1 are the major players in drug efflux-mediated multidrug resistance (MDR), which severely affects the efficacy of chemotherapy. Several synthetic compounds block the drug transport by ABC transporters; however, they exhibit a narrow therapeutic window, and produce side effects in non-target normal tissues. Conversely, the downregulation of the expression of ABC drug transporters seems to be a promising strategy to reverse MDR in cancer cells. Several signaling pathways, such as NF-κB, STAT3, Gli, NICD, YAP/TAZ, and Nrf2 upregulate the expression of ABC drug transporters in drug-resistant cancers. Recently, natural medicinal compounds have gained importance to overcome the ABC drug-efflux pump-mediated MDR in cancer. These compounds target transcription factors and the associated signal transduction pathways, thereby downregulating the expression of ABC transporters in drug-resistant cancer cells. Several potent natural compounds have been identified as lead candidates to synergistically enhance chemotherapeutic efficacy, and a few of them are already in clinical trials. Therefore, modulation of signal transduction pathways using natural medicinal compounds for the reversal of ABC drug transporter-mediated MDR in cancer is a novel approach for improving the efficiency of the existing chemotherapeutics. In this review, we discuss the modulatory role of natural medicinal compounds on cellular signaling pathways that regulate the expression of ABC transporters in drug-resistant cancer cells. • ATP-binding cassette (ABC) transporters are the major players of multidrug resistance (MDR). • Signaling pathways upregulate the expression of ABC drug transporters in drug-resistant cancers. • Downregulation of the expression of ABC drug transporter reverses drug resistance in MDR cancer cells. • Natural medicinal compounds downregulates the expression of ABC transporters in drug-resistant cancer cells. • Natural medicinal compounds could be used as chemosensitizers to overcome ABC transporters mediated drug-resistance. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Enhanced delivery of quercetin and doxorubicin using β-cyclodextrin polymer to overcome P-glycoprotein mediated multidrug resistance.
- Author
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Pawar, Charan Singh, Rajendra Prasad, N., Yadav, Priya, Muthu Vijayan Enoch, I.V., Manikantan, Varnitha, Dey, Bindiya, and Baruah, Paran
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P-glycoprotein , *MULTIDRUG resistance , *CYCLODEXTRINS , *QUERCETIN , *POLYMERS , *CANCER cells , *DOXORUBICIN - Abstract
Synthesis of β -CDP/QD NCs using epichlorohydrin linker to overcome. P-glycoprotein (P-gp) mediated MDR in cancer cells. The β -CDP/QD NCs enter the MDR cancer cells through endocytosis. The QCT released from the nanocarrier enhances the intracellular availability of DOX via blocking the drug efflux function of P-gp. [Display omitted] • The β -CDP/QD NCs were successfully synthesized by the freeze-dried method. • Spectroscopic and microscopic studies evaluate the encapsulation of drugs in polymer. • The β -CDP/QD NCs show burst and sustained release of quercetin and doxorubicin. • β -CDP/QD NCs show enhanced apoptotic cell death in MDR cancer cells. In this study, we prepared a β -cyclodextrin polymer (β -CDP) co-loaded quercetin (QCT) and doxorubicin (DOX) nanocarrier (β -CDP/QD NCs) by freeze-dried method to combat P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in KB-ChR 8–5 cancer cells. Various microscopic and spectroscopic techniques were employed to characterize the prepared nanocarrier. The molecular docking studies confirm the effective binding interactions of QCT and DOX with the synthesized β -CD polymer. The in vitro drug release study illustrates the sustainable release of DOX and QCT from the β -CDP nanocarrier. Further, we noticed that the QCT released from the β -CDP nanocarrier improved the intracellular availability of DOX via modulating P-gp drug efflux function in KB-ChR 8–5 cells and MCF-7/DOX cancer cells. Cell uptake results confirmed the successful internalization of DOX in KB-ChR 8–5 cells compared with free DOX. Cell-based assays such as nuclear condensation, alteration in the mitochondrial membrane potential (MMP), and apoptosis morphological changes confirmed the enhanced anticancer effect of β -CDP/QD NCs in the resistant cancer cells. Hence, QCT and DOX co-loaded β -CDP may be considered effective in achieving maximum cell death in the P-gp overexpressing MDR cancer cells. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Solasodine targets NF-κB signaling to overcome P-glycoprotein mediated multidrug resistance in cancer.
- Author
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Bharathiraja, Pradhapsingh, Balamurugan, Karankumar, Govindasamy, Chandramohan, Prasad, N. Rajendra, and Pore, Pranjali Milind
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P-glycoprotein , *MULTIDRUG resistance , *DOXORUBICIN , *STEROIDAL alkaloids , *TREATMENT effectiveness , *CELL populations , *DRUG resistance - Abstract
P-glycoprotein (P-gp) mediated multidrug resistance (MDR) is the leading cause of chemotherapy failure since it causes the efflux of chemotherapeutic drugs from the cancer cells. Solasodine, a steroidal alkaloid and oxaspiro compound, present in the Solanaceae family showed significant cytotoxic effects on various cancer cells. However, the effect of solasodine on reversing P-gp mediated drug resistance is still unknown. Primarily in this study, the integrative network pharmacology analysis found 71 common targets between solasodine and cancer MDR, among them NF-κB was found as a potential target. The results of immunofluorescence analysis showed that solasodine significantly inhibits NF-κB-p65 nuclear translocation which caused downregulated P-gp expression in KBChR-8-5 cells. Further, solasodine binds to the active sites of the TMD region of P-gp and inhibits P-gp transport activity. Moreover, solasodine significantly promotes doxorubicin intracellular accumulation in the drug resistant cells. Solasodine reduced the fold resistance and synergistically sensitized doxorubicin's therapeutic effects in KBChR-8-5 cells. Additionally, the solasodine and doxorubicin combination treatment increased the apoptotic cell populations and G2/M phase cell cycle arrest in KBChR-8-5 cells. The MDR tumor bearing xenograft mice showed tumor-suppressing characteristics and P-gp downregulation during the combination treatment of solasodine and doxorubicin. These results indicate that solasodine targets NF-κB signaling to downregulate P-gp overexpression, inhibit P-gp transport activity, and enhance chemosensitization in MDR cancer cells. Considering its multifaceted impact, solasodine represents a potent natural fourth-generation P-gp modulator for reversing MDR in cancer. [Display omitted] • Solasodine effectively reversed P-glycoprotein (P-gp) mediated multidrug resistance in KBChR-8-5 cancer cells. • Solasodine inhibits NF-κB signaling pathway which downregulates P-gp overexpression in KBChR-8-5 cells. • Solasodine actively binds to the P-gp drug binding pocket and inhibits its drug efflux activity. • In combination with doxorubicin, solasodine synergistically enhanced the chemosensitivity of doxorubicin in KBChR-8-5 cells. • Moreover, solasodine and doxorubicin combination suppressed the tumor growth in MDR tumor bearing nude mice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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