Volasertib (BI 6727), a novel polo-like kinase inhibitor, reverses ABCB1 and ABCG2-mediated multidrug resistance in cancer cells

To, Kenneth Kin Wah; Poon, Daniel C.; Chen, X.G.; Li, Fu

doi:10.7243/2049-7962-2-13

Cited by 8 publications

(12 citation statements)

References 27 publications

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“…Since drug transporter efflux activity is associated with ATP hydrolysis, they further investigated ABC‐B1 and ABC‐G2 inhibition upon BI6727 treatment using an ATPase assay. The results from these experiments indicated that BI6727 reversed ABC‐B1‐mediated MDR by inhibition of the ATP hydrolysis, while volasertib could also act as a competitive inhibitor substrate for the ABC‐G2 transporter . In contrast, Wu et al .…”

Section: Volasertib Monotherapymentioning

confidence: 87%

“…The results from these experiments indicated that BI6727 reversed ABC-B1-mediated MDR by inhibition of the ATP hydrolysis, while volasertib could also act as a competitive inhibitor substrate for the ABC-G2 transporter. 80 In contrast, Wu et al 81 found that overexpression of the ABC-B1 transporter leads to cellular resistance to volasertib treatment. For example, ABC-B1 overexpressing human epidermal cells (KB-V-1) were significantly less sensitive to the Plk1 inhibitor compared with parental cells, which was confirmed by a significant decrease in volasertib-stimulated mitotic cell cycle arrest and subsequent induction of apoptosis.…”

Section: Volasertib and Resistance To Anticancer Therapiesmentioning

confidence: 98%

“…A synergistic cytotoxic effect was also observed for the combination of volasertib plus paclitaxel in SW620 colon carcinoma cancer cells. While volasertib monotherapy (20 nM) induced only mild apoptosis, simultaneous treatment with volasertib plus paclitaxel (50 nM) for 48 hr caused a considerable increase in the amount of apoptotic SW620 cells . Recently, the research on combination treatment between volasertib and microtubule interfering drugs was expanded.…”

Section: Volasertib In Combination Studiesmentioning

confidence: 99%

“…Interestingly, in vitro tests using volasertib showed promising antitumor activity in cell lines resistant to taxanes and vinca alkaloids and in a melanoma cell line that expressed the multidrug resistance (MDR) 1 gene. 52 The publication of To et al 80 in 2013 on volasertib and MDR provided a first insight into the underlying mechanism. MDR is often caused by the recognition and active efflux of toxic agents by ATP-binding cassette (ABC) transporters such as ABC-B1, ABC-C1, and ABC-G2.…”

Section: Volasertib and Resistance To Anticancer Therapiesmentioning

confidence: 99%

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Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Bossche

Lardon

Deschoolmeester

et al. 2016

Medicinal Research Reviews

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Considering the important side effects of conventional microtubule targeting agents, more and more research focuses on regulatory proteins for the development of mitosis-specific agents. Polo-like kinase 1 (Plk1), a master regulator of several cell cycle events, has arisen as an intriguing target in this research field. The observed overexpression of Plk1 in a broad range of human malignancies has given rise to the development of several potent and specific small molecule inhibitors targeting the kinase. In this review, we focus on volasertib (BI6727), the lead agent in category of Plk1 inhibitors at the moment. Numerous preclinical experiments have demonstrated that BI6727 is highly active across a variety of carcinoma cell lines, and the inhibitor has been reported to induce tumor regression in several xenograft models. Moreover, volasertib has shown clinical efficacy in multiple tumor types. As a result, Food and Drug Administration (FDA) has recently awarded volasertib the Breakthrough Therapy status after significant benefit was observed in acute myeloid leukemia (AML) patients treated with the Plk1 inhibitor. Here, we discuss both preclinical and clinical data available for volasertib administered as monotherapy or in combination with other anticancer therapies in a broad range of tumor types.

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Section: Volasertib Monotherapymentioning

confidence: 87%

Section: Volasertib and Resistance To Anticancer Therapiesmentioning

confidence: 98%

Section: Volasertib In Combination Studiesmentioning

confidence: 99%

Section: Volasertib and Resistance To Anticancer Therapiesmentioning

confidence: 99%

See 2 more Smart Citations

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Bossche

Lardon

Deschoolmeester

et al. 2016

Medicinal Research Reviews

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“…The recent discovery that TKIs can potently and specifically inhibit various ABC transporters has advocated the use of TKIs as chemosensitizers to circumvent MDR. In this regard, we have previously demonstrated that apatinib (Mi et al ., ; Tong et al ., ), axitinib (Wang et al ., ), crizotinib (Zhou et al ., ), vandetanib (Zheng et al ., ) and volasertib (To et al ., ) inhibit various ABC transporters and reverse MDR in leukaemia and solid tumours.…”

Section: Introductionmentioning

confidence: 99%

Pelitinib (EKB‐569) targets the up‐regulation of ABCB1 and ABCG2 induced by hyperthermia to eradicate lung cancer

Poon

Wei

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEPelitinib is a potent irreversible EGFR TK inhibitor currently in clinical trials for the treatment of lung cancer. Hyperthermia has been applied concomitantly with chemotherapy and radiotherapy to enhance treatment outcome. In this study, we investigated the ability of the combination of pelitinib with other conventional anticancer drugs to specifically target cancer cells with up-regulated efflux transporters ABCB1/ABCG2 after hyperthermia as a novel way to eradicate the cancer stem-like cells responsible for cancer recurrence. EXPERIMENTAL APPROACHAlterations in intracellular topotecan accumulation, the efflux of fluorescent probe substrates, expression and ATPase activity of ABCB1/ABCG2 and tumoursphere formation capacity of side population (SP) cells sorted after hyperthermia were examined to elucidate the mechanism of pelitinib-induced chemosensitization. KEY RESULTSWhile pelitinib did not modulate ABCB1/ABCG2 expressions, the combination of pelitinib with transporter substrate anticancer drugs induced more marked apoptosis, specifically in cells exposed to hyperthermia. The flow cytometric assay showed that both ABCB1-and ABCG2-mediated drug effluxes were significantly inhibited by pelitinib in a concentration-dependent manner. The inhibition kinetics suggested that pelitinib is a competitive inhibitor of ABCB1/ABCG2, which is consistent with its ability to stimulate their ATPase activity. SP cells sorted after hyperthermia were found to be more resistant to anticancer drugs, presumably due to the up-regulation of ABCB1 and ABCG2. Importantly, pelitinib specifically enhanced the chemosensitivity but reduced the tumoursphere formation capacity of these SP cells. CONCLUSIONS AND IMPLICATIONSThis study demonstrated a novel approach, exploiting drug resistance, to selectively kill cancer stem-like cells after hyperthermia. AbbreviationsABC, ATP-binding cassette; CSC, cancer stem-like cell; FTC, fumitremorgin C; HSE, heat shock element; MDR, multidrug resistance; NSP, non-SP population; PhA, pheophorbide A; Rh123, rhodamine 123; SP, side population BJP IntroductionThe large family of ATP-binding cassette (ABC) transporters, including P-glycoprotein (ABCB1/P-gp), ABCC1/MRP1 and ABCG2, play a key role in the energy-dependent cellular efflux of chemotherapeutic drugs. They are capable of recognizing and extruding a broad range of structurally and functionally unrelated anticancer drugs, thereby leading to multidrug resistance (MDR) in cancer cells. Cancer recurrence is a major hurdle hindering successful chemotherapy. It is believed to arise from the survival of cancer stem-like cells (CSCs) after anticancer treatment. To this end, cancer stemlike phenotypes are correlated with elevated expression of the efflux transporters ABCB1 and/or ABCG2 (Ho et al., 2007), which protect the cancer cells from chemotherapy. Therefore, substantial research efforts have been made to target these CSCs to eliminate metastasis and prevent recurrence (Frank et al., 2010;Takebe et al., 2011). TK inhibitors (TKI...

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Small Molecule Chemosensitizing Agents: Polo-Like Kinase 1 (Plk1), BRAF and Janus Kinase (JAK) Inhibitors

Hsu

2019

Protein Kinase Inhibitors as Sensitizing Agents for Chemotherapy

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Volasertib (BI 6727), a novel polo-like kinase inhibitor, reverses ABCB1 and ABCG2-mediated multidrug resistance in cancer cells

Cited by 8 publications

References 27 publications

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Pelitinib (EKB‐569) targets the up‐regulation of ABCB1 and ABCG2 induced by hyperthermia to eradicate lung cancer

Small Molecule Chemosensitizing Agents: Polo-Like Kinase 1 (Plk1), BRAF and Janus Kinase (JAK) Inhibitors

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