Tyrosine Kinase Inhibitors as Reversal Agents for ABC Transporter Mediated Drug Resistance

Anreddy, Nagaraju; Gupta, Pranav; Kathawala, Rishil J.; Patel, Atish; Wurpel, John N.D.; Chen, Zhe‐Sheng

doi:10.3390/molecules190913848

Cited by 105 publications

(75 citation statements)

References 150 publications

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“…Acquired drug resistance of cancer cells leads to the failure of chemotherapy (12). In BCa, cisplatin is regarded as the most effective components of classical chemoregimen, such as M-AVC regimen; however, BCa cell acquired resistance to the treatment leads to inevitable tumor progression (21).…”

Section: Resultsmentioning

confidence: 99%

“…To date, 49 members of ABC superfamily has been discovered and divided into 7 subfamilies according to their structure (ABCA to ABCG) (11), among of them, ʻABCB1ʼ (MDR1/P-gp) is regarded as the main one due to its special role in chemoresistance. MDR1 is a 170 kDa protein and consists of two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs), which localize in apical membrane of kidney, placenta, liver, adrenal glands, intestine and blood-brain barrier cells (12). Overexpression of MDR1 has been associated with various types of cancers, such as acute myeloid leukemia, childhood tumors, breast cancers and hematological malignancies, which can be regulated by tumor-related signaling, such as PI3K/Akt signaling (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

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HIF-1α/MDR1 pathway confers chemoresistance to cisplatin in bladder cancer

et al. 2015

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Abstract. Bladder cancer (BCa) is the 9th most common malignant tumor and the 13th leading cause of death due to cancer. The development of surgery and target drugs bring new challenges for the traditional concept for BCa therapy, and chemotherapy is still the final option for many BCa patients, and cisplatin-containing regimen the most effective one. However, the ubiquitous application of cisplatin-containing regimen in BCa results in the cisplatin-resistance, in addition, the cisplatin-resistant BCa manifests enhanced malignant behavior, the mechanism of which is unclear. In the present study, we used BCa cell lines to to clarify this point. BCa cell lines T24/J82 were pretreated with cisplatin >3 months to construct stable cisplatin-resistant cell lines (tagged T24Cis-R and J82Cis-R ), which manifested as enhanced capacity of proliferation and malignant behavior in vivo and in vitro, accompanied by cisplatin, and even doxorubicin resistance. The following mechanism dissection revealed that prolonged treatment time of T24/J82 cells led to elevated expression of HIF-1α, which targeted the increased expression of MDR1 on the one hand, and contributed to BCa cell proliferation, migration/invasion on the other hand. Finally, IHC staining of human BCa tissue supported our conclusion that the expression of HIF-1α and MDR1 was higher in chemoresistant tissue vs. chemosensitive tissue. Our results provided a new view of HIF-1α in chemotherapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HIF-1α/MDR1 pathway confers chemoresistance to cisplatin in bladder cancer

et al. 2015

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“…One of the main obstacles of cancer chemotherapeutics is chemo-resistance, especially the acquired chemoresistance, leading to failure of the treatments against cancer (8,9), and BCa is not an exception. As the final regimen for BCa patients, efficiency of chemotherapy plays a decisive role in BCa prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…ATP-binding cassette (ABC) family, the vital ATP-dependent transporter located in cell membrane, is gaining interest in the process of mechanical investigation of chemoresistance in BCa therapy (8,9). ABC transporters 'pump' drugs, such as anti-neoplastic drugs, out of the cells against a concentration gradient, this is the basic mechanism of chemoresistance (10).…”

Section: Introductionmentioning

confidence: 99%

NF-κB signaling plays irreplaceable roles in cisplatin-induced bladder cancer chemoresistance and tumor progression

Sun

Guan

Liang

et al. 2015

International Journal of Oncology

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Abstract. Bladder cancer (BCa) is the most vital urogenital malignant disease worldwide, bringing huge economic and social burden every year. Clinically, BCa is subdivided into superficial type and invasive type according to clinicpathology, accompanied with different strategy of therapy. Number of reports indicate that 10-30% of superficial BCa will inevitable progress into invasive type, manifesting enhanced malignant behavior compared to original invasive type. Regardless of the original being an original invasive type or invasive type that progressed from superficial type of BCa, chemotherapy (including adjuvant or neo-adjuvant chemotherapy) in line with radiotherapy is the final regimen for BCa patients. Previous reports pointed out the high efficiency of cisplatin-containing chemotherapeutic regimen for BCa patients, leading to wide use of this regimen in BCa therapeutics. However, cisplatin-resistance inevitably appear, resulting in the failure of the BCa chemotherapy, the mechanism of which is still unknown. In the present study, parental BCa cell lines T24/J82 were used to obtain stable-cisplatinresistance cell lines T24 R /J82 R , which showed enhanced capacity of malignancy, tumorigenesis and drug resistance, accompanied by elevated expression of EMT markers. The further mechanism investigation suggested that prolonged time of cisplatin-treatment contributed to the activation of the NF-κB signal, resulting in the upregulation of EMT markers, the maintenance of stem cell marker and the elevated expression of ABCB1. Thus, our study provides us a new view of the role of NF-κB signaling in BCa therapeutics.

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“…Establishment of SN-38-resistant cell lines Table 1 summarizes the IC 50 values of the parental cell lines (MDA-MB-231 and NCI-N87) and their SN-38-resistant counterparts (MDA-MB-231-S120 and NCI-N87-S120), as determined for SN-38, doxorubicin and paclitaxel. Compared with the parental cells, both S120 cells are about 50-fold more resistant to SN-38 and relatively not cross-resistant to either doxorubicin or paclitaxel.…”

Section: Resultsmentioning

confidence: 99%

Combining ABCG2 Inhibitors with IMMU-132, an Anti–Trop-2 Antibody Conjugate of SN-38, Overcomes Resistance to SN-38 in Breast and Gastric Cancers

Chang

Wang

Zalath

et al. 2016

Molecular Cancer Therapeutics

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Sacituzumab govitecan , an SN-38-conjugated antibody-drug conjugate, is showing promising therapeutic results in a phase I/II trial of patients with advanced Trop-2-expressing, metastatic, solid cancers. As members of the ATPbinding cassette (ABC) transporters confer chemotherapy resistance by active drug efflux, which is a frequent cause of treatment failure, we explored the use of known inhibitors of ABC transporters for improving the therapeutic efficacy of IMMU-132 by overcoming SN-38 resistance. Two human tumor cell lines made resistant to SN-38, MDA-MB-231-S120 (human breast cancer) and NCI-N87-S120 (human gastric cancer), were established by continuous exposure of the parental cells to stepwise increased concentrations of SN-38 and analyzed by flow cytometry for functional activities of ABCG2 and ABCB1, immunoblotting and qRT-PCR for the expression of ABCG2 at both protein and mRNA levels, and MTS assays for the potency of SN-38 alone or in combination with a modulator of ABC transporters. MDA-MB-231-S120 and NCI-N87-S120 displayed reduced sensitivity to SN-38 in vitro, with IC 50 values approximately 50-fold higher than parental MDA-MB-231 and NCI-N87 cells. The increase in drug resistance of both S120 cell populations is associated with the expression of functional ABCG2, but not ABCB1. Importantly, treatment of both S120 sublines with known ABCG2 inhibitors (fumitremorgin C, Ko143, and YHO-13351) restored toxicity of SN-38, and the combination of YHO-13351 with IMMU-132 increased the median survival of mice bearing NCI-N87-S120 xenografts. These results provide a rationale for combination therapy of IMMU-132 and inhibitors of ABC transporters, such as YHO-13351.

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Tyrosine Kinase Inhibitors as Reversal Agents for ABC Transporter Mediated Drug Resistance

Cited by 105 publications

References 150 publications

HIF-1α/MDR1 pathway confers chemoresistance to cisplatin in bladder cancer

HIF-1α/MDR1 pathway confers chemoresistance to cisplatin in bladder cancer

NF-κB signaling plays irreplaceable roles in cisplatin-induced bladder cancer chemoresistance and tumor progression

Combining ABCG2 Inhibitors with IMMU-132, an Anti–Trop-2 Antibody Conjugate of SN-38, Overcomes Resistance to SN-38 in Breast and Gastric Cancers

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