Anticancer and Reversing Multidrug Resistance Activities of Natural Isoquinoline Alkaloids and their Structure-activity Relationship

2019 ◽  
Vol 25 (38) ◽  
pp. 5088-5114 ◽  
Author(s):  
Zhi-Xing Qing ◽  
Jia-Lu Huang ◽  
Xue-Yi Yang ◽  
Jing-Hong Liu ◽  
Hua-Liang Cao ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Anticancer Drugs ◽  
Multidrug Resistant ◽  
Isoquinoline Alkaloid ◽  
Positive Control ◽  
Isoquinoline Alkaloids ◽  
Anticancer Activities ◽  
Lead Compounds ◽  
Structure Activity ◽  
Chemotherapy Agents

The severe anticancer situation as well as the emergence of multidrug-resistant (MDR) cancer cells has created an urgent need for the development of novel anticancer drugs with different mechanisms of action. A large number of natural alkaloids, such as paclitaxel, vinblastine and camptothecin have already been successfully developed into chemotherapy agents. Following the success of these natural products, in this review, twenty-six types of isoquinoline alkaloids (a total of 379 alkaloids), including benzyltetrahydroisoquinoline, aporphine, oxoaporphine, isooxoaporphine, dimeric aporphine, bisbenzylisoquinoline, tetrahydroprotoberberine, protoberberine, protopine, dihydrobenzophenanthridine, benzophenanthridine, benzophenanthridine dimer, ipecac, simple isoquinoline, pavine, montanine, erythrina, chelidonine, tropoloisoquinoline, azafluoranthene, phthalideisoquinoline, naphthylisoquinoline, lycorine, crinane, narciclasine, and phenanthridone, were summarized based on their cytotoxic and MDR reversing activities against various cancer cells. Additionally, the structure-activity relationships of different types of isoquinoline alkaloid were also discussed. Interestingly, some aporphine, oxoaporphine, isooxoaporphine, bisbenzylisoquinoline, and protoberberine alkaloids display more potent anticancer activities or anti-MDR effects than positive control against the tested cancer cells and are regarded as attractive targets for discovery new anticancer drugs or lead compounds.

scholarly journals Evaluation the effect of several anticancer drugs on Vietnamese breast cancer cells

2018 ◽  
Vol 21 (2) ◽  
pp. 44-51
Author(s):  
Oanh Thi-Kieu Nguyen
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Breast Cancer Cells ◽  
Multidrug Resistant ◽  
Positive Control ◽  
Breast Cancer Patients ◽  
Ic50 Value ◽  
Very High ◽  
Mcf 7

In Viet Nam, data from Conference of Cancer organized by the Ministry of Health has shown that breast cancer is the most popular cancer in women. Current mainly treatments are surgery, chemotherapy, and radiotherapy. However, the rate of recurrence after five years was very high. One of the causes of high relapse is cancer cells develop multidrug-resistant (MDR) thus reduced the efficiency of treatments. In this research, MTT assay was used for measured cell viability of Vietnamese breast cancer cells (VNBRCA cells) and positive control MCF-7 cell lines after treatment with several anticancer drugs as Doxorubicin (DOX), Tamoxifen (TAM), Mitomycin C (MMC) in 48h. After that, cancer cells were treated at haft maximal inhibitory concentration (IC50) of anticancer drug and observed cell morphology, apoptosis of cellular nuclear by AO/PI staining. IC50 value of VNBRCA cells with DOX, TAM, MMC were 0.641± 0.07 µM, 4.639 ± 0.933 µM and 1.338 ± 0.176 µM, respectively, which higher than IC50 of MCF-7 with DOX, TAM, MMC was 0.168 ± 0.037 µM, 7.085 ± 0.87 µM and 0.379 ± 0.159 µM, respectively. The response of VNBRCA cells with several anticancer drugs as DOX, TAM, and MMC was lower than the response of MCF-7, therefore, it showed that the specific features of VNBRCA cells; from which develop specific treatments for Vietnamese breast cancer patients.

scholarly journals Suppression of αvβ6 downregulates P-glycoprotein and sensitizes multidrug-resistant breast cancer cells to anticancer drugs

Neoplasma ◽  
2020 ◽  
Vol 67 (02) ◽  
pp. 379-388 ◽  
Author(s):  
Y.H. ZHANG ◽  
Z.F. GAO ◽  
G.H. DONG ◽  
X. LI ◽  
Y. WU ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Breast Cancer Cells ◽  
Multidrug Resistant ◽  
P Glycoprotein

scholarly journals The Selective Class IIa Histone Deacetylase Inhibitor TMP195 Resensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs

2019 ◽  
Vol 21 (1) ◽  
pp. 238 ◽  
Author(s):  
Chung-Pu Wu ◽  
Sabrina Lusvarghi ◽  
Jyun-Cheng Wang ◽  
Sung-Han Hsiao ◽  
Yang-Hui Huang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Histone Deacetylase ◽  
Anticancer Drugs ◽  
Drug Transport ◽  
Drug Repurposing ◽  
Binding Pocket ◽  
Multidrug Resistant ◽  
Drug Induced ◽  
In Silico Docking

Multidrug resistance caused by the overexpression of the ATP-binding cassette (ABC) proteins in cancer cells remains one of the most difficult challenges faced by drug developers and clinical scientists. The emergence of multidrug-resistant cancers has driven efforts from researchers to develop innovative strategies to improve therapeutic outcomes. Based on the drug repurposing approach, we discovered an additional action of TMP195, a potent and selective inhibitor of class IIa histone deacetylase. We reveal that in vitro TMP195 treatment significantly enhances drug-induced apoptosis and sensitizes multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2 to anticancer drugs. We demonstrate that TMP195 inhibits the drug transport function, but not the protein expression of ABCB1 and ABCG2. The interaction between TMP195 with these transporters was supported by the TMP195-stimulated ATPase activity of ABCB1 and ABCG2, and by in silico docking analysis of TMP195 binding to the substrate-binding pocket of these transporters. Furthermore, we did not find clear evidence of TMP195 resistance conferred by ABCB1 or ABCG2, suggesting that these transporters are unlikely to play a significant role in the development of resistance to TMP195 in cancer patients.

scholarly journals Shikonin Directly Targets Mitochondria and Causes Mitochondrial Dysfunction in Cancer Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Benjamin Wiench ◽  
Tolga Eichhorn ◽  
Malte Paulsen ◽  
Thomas Efferth
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Cell Lines ◽  
Inflammatory Diseases ◽  
Multidrug Resistant ◽  
Resistant Cell ◽  
Live Cells ◽  
Anticancer Activities ◽  
Cycle Arrest ◽  
Therapy Success

Chemotherapy is a mainstay of cancer treatment. Due to increased drug resistance and the severe side effects of currently used therapeutics, new candidate compounds are required for improvement of therapy success. Shikonin, a natural naphthoquinone, was used in traditional Chinese medicine for the treatment of different inflammatory diseases and recent studies revealed the anticancer activities of shikonin. We found that shikonin has strong cytotoxic effects on 15 cancer cell lines, including multidrug-resistant cell lines. Transcriptome-wide mRNA expression studies showed that shikonin induced genetic pathways regulating cell cycle, mitochondrial function, levels of reactive oxygen species, and cytoskeletal formation. Taking advantage of the inherent fluorescence of shikonin, we analyzed its uptake and distribution in live cells with high spatial and temporal resolution using flow cytometry and confocal microscopy. Shikonin was specifically accumulated in the mitochondria, and this accumulation was associated with a shikonin-dependent deregulation of cellular Ca2+and ROS levels. This deregulation led to a breakdown of the mitochondrial membrane potential, dysfunction of microtubules, cell-cycle arrest, and ultimately induction of apoptosis. Seeing as both the metabolism and the structure of mitochondria show marked differences between cancer cells and normal cells, shikonin is a promising candidate for the next generation of chemotherapy.

scholarly journals Comparative Study on the MDR Reversal Effects of Selected Chalcones

2011 ◽  
Vol 2011 ◽  
pp. 1-7
Author(s):  
A. B. Ivanova ◽  
D. I. Batovska ◽  
I. T. Todorova ◽  
B. A. Stamboliyska ◽  
J. Serly ◽  
...  
Keyword(s):  
Positive Control ◽  
The Other ◽  
Lymphoma Cells ◽  
Lead Compounds ◽  
Structure Activity ◽  
Mouse Lymphoma Cells ◽  
Human Mdr1 ◽  
Mouse Lymphoma ◽  
Mdr Reversal

Based on the structure of three previously established lead compounds, fifteen selected chalcones were synthesized and evaluated for their multidrug resistance (MDR) reversal activity on mouse lymphoma cells. The most active chalcones were stronger revertants than the positive control, verapamil. In the model of combination chemotherapy, the interactions between the anticancer drug doxorubicin and two of the most effective compounds were measured in vitro, on human MDR1 gene transfected mouse lymphoma cells, showing that the type of interaction for one of these compounds was indifferent while that for the other one was additive. Furthermore, two chalcones inhibited 50% of cell proliferation in concentration of around 0.4 μg/mL and were from 2- to 100-fold more active than the most chalcones. The structure-activity relationships were obtained and discussed in view of their usefulness for the design of chalcone-like P-gp modulators and drugs able to treat resistant cancers.

scholarly journals 20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs

2013 ◽  
Vol 21 (14) ◽  
pp. 4279-4287 ◽  
Author(s):  
Junhua Liu ◽  
Xu Wang ◽  
Peng Liu ◽  
Rongxin Deng ◽  
Min Lei ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Anticancer Drugs ◽  
Multidrug Resistant

scholarly journals The Second-Generation PIM Kinase Inhibitor TP-3654 Resensitizes ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs

2021 ◽  
Vol 22 (17) ◽  
pp. 9440
Author(s):  
Chung-Pu Wu ◽  
Yan-Qing Li ◽  
Ya-Chen Chi ◽  
Yang-Hui Huang ◽  
Tai-Ho Hung ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Anticancer Drugs ◽  
Drug Transport ◽  
Second Generation ◽  
Kinase Inhibitor ◽  
Multidrug Resistant ◽  
Drug Efflux ◽  
Transport Function ◽  
Therapy Option ◽  
Induction Of Resistance

Human ATP-binding cassette (ABC) subfamily G member 2 (ABCG2) mediates the transport of a wide variety of conventional cytotoxic anticancer drugs and molecular targeted agents. Consequently, the overexpression of ABCG2 in cancer cells is linked to the development of the multidrug resistance (MDR) phenotype. TP-3654 is an experimental second-generation inhibitor of PIM kinase that is currently under investigation in clinical trials to treat advanced solid tumors and myelofibrosis. In this study, we discovered that by attenuating the drug transport function of ABCG2, TP-3654 resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic ABCG2 substrate drugs topotecan, SN-38 and mitoxantrone. Moreover, our results indicate that ABCG2 does not mediate resistance to TP-3654 and may not play a major role in the induction of resistance to TP-3654 in cancer patients. Taken together, our findings reveal that TP-3654 is a selective, potent modulator of ABCG2 drug efflux function that may offer an additional combination therapy option for the treatment of multidrug-resistant cancers.

scholarly journals Erdafitinib Resensitizes ABCB1-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1366
Author(s):  
Chung-Pu Wu ◽  
Tai-Ho Hung ◽  
Sung-Han Hsiao ◽  
Yang-Hui Huang ◽  
Lang-Cheng Hung ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Anticancer Drugs ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Binding Pocket ◽  
Multidrug Resistant ◽  
In Silico Docking ◽  
Major Mechanism ◽  
Therapeutic Drugs ◽  
Future Drug

The development of multidrug resistance (MDR) in cancer patients, which is often associated with the overexpression of ABCB1 (MDR1, P-glycoprotein) in cancer cells, remains a significant problem in cancer chemotherapy. ABCB1 is one of the major adenosine triphosphate (ATP)-binding cassette (ABC) transporters that can actively efflux a range of anticancer drugs out of cancer cells, causing MDR. Given the lack of Food and Drug Administration (FDA)-approved treatment for multidrug-resistant cancers, we explored the prospect of repurposing erdafitinib, the first fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the FDA, to reverse MDR mediated by ABCB1. We discovered that by reducing the function of ABCB1, erdafitinib significantly resensitized ABCB1-overexpressing multidrug-resistant cancer cells to therapeutic drugs at sub-toxic concentrations. Results of erdafitinib-stimulated ABCB1 ATPase activity and in silico docking analysis of erdafitinib binding to the substrate-binding pocket of ABCB1 further support the interaction between erdafitinib and ABCB1. Moreover, our data suggest that ABCB1 is not a major mechanism of resistance to erdafitinib in cancer cells. In conclusion, we revealed an additional action of erdafitinib as a potential treatment option for multidrug-resistant cancers, which should be evaluated in future drug combination trials.

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