Overcoming Taxol-resistance in A549 cells: A comprehensive strategy of targeting P-gp transporter, AKT/ERK pathways, and cytochrome P450 enzyme CYP1B1 by 4-hydroxyemodin

Lin, Hao; Hu, Baichun; He, Xiaomei; Mao, Jianping; Wang, Ying; Wang, Jian; Zhang, Tingting; Zheng, Jiang; Peng, Ying; Zhang, Fengjiao

doi:10.1016/j.bcp.2019.113733

Cited by 31 publications

(26 citation statements)

References 66 publications

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“…The P-gp is expressed in a number of barriers including the blood-brain barrier (BBB), blood-testis barrier (BTB), and blood-cerebrospinal fluid barrier to modulate absorption and excretion of xenobiotics [359]. Although normal activity of P-gp is vital in physiological conditions, its upregulation is an increasing impediment in cancer therapy, since cancer cells are able to trigger chemoresistance by enhancing expression of P-gp [360,361]. As mentioned earlier, administration of CP has been correlated with stimulation of EMT.…”

Section: Targeting Drug Transportersmentioning

confidence: 99%

Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

Ashrafizadeh

Zarrabi

Hushmandi

et al. 2020

IJMS

191

103

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Therapy resistance is a characteristic of cancer cells that significantly reduces the effectiveness of drugs. Despite the popularity of cisplatin (CP) as a chemotherapeutic agent, which is widely used in the treatment of various types of cancer, resistance of cancer cells to CP chemotherapy has been extensively observed. Among various reported mechanism(s), the epithelial–mesenchymal transition (EMT) process can significantly contribute to chemoresistance by converting the motionless epithelial cells into mobile mesenchymal cells and altering cell–cell adhesion as well as the cellular extracellular matrix, leading to invasion of tumor cells. By analyzing the impact of the different molecular pathways such as microRNAs, long non-coding RNAs, nuclear factor-κB (NF-ĸB), phosphoinositide 3-kinase-related protein kinase (PI3K)/Akt, mammalian target rapamycin (mTOR), and Wnt, which play an important role in resistance exhibited to CP therapy, we first give an introduction about the EMT mechanism and its role in drug resistance. We then focus specifically on the molecular pathways involved in drug resistance and the pharmacological strategies that can be used to mitigate this resistance. Overall, we highlight the various targeted signaling pathways that could be considered in future studies to pave the way for the inhibition of EMT-mediated resistance displayed by tumor cells in response to CP exposure.

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Section: Targeting Drug Transportersmentioning

confidence: 99%

Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

Ashrafizadeh

Zarrabi

Hushmandi

et al. 2020

IJMS

191

103

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“…Additionally, STAT3 plays significant role in transcriptional regulation of P-GP expression (Wang R. et al, 2020). As mentioned in previous studies, targeting P-GP transporter is a viable strategy to overcome paclitaxel resistance in A549 cells (Lin et al, 2020). Therefore, we were interested in determining whether these two SLs members have the capability to downregulate P-GP expression among A549/T cells.…”

Section: Alt and Brv-a Inhibit Stat3 Activation And Attenuate Fut4 An...mentioning

confidence: 98%

Sesquiterpene Lactones Attenuate Paclitaxel Resistance Via Inhibiting MALAT1/STAT3/ FUT4 Axis and P-Glycoprotein Transporters in Lung Cancer Cells

et al. 2022

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Paclitaxel resistance is a challenging factor in chemotherapy resulting in poor prognosis and cancer recurrence. Signal transducer and activator of transcription factor 3 (STAT3), a key transcription factor, performs a critical role in cancer development, cell survival and chemoresistance, while its inactivation overwhelms drug resistance in numerous cancer types including lung cancer. Additionally, the fucosyltransferase 4 (FUT4) is a crucial enzyme in post-translational modification of cell-surface proteins involved in various pathological conditions such as tumor multidrug resistance (MDR). The P-glycoprotein (P-GP) is the well-known ABC transporter member that imparts drug resistance in different cancer types, most notably paclitaxel resistance in lung cancer cells. LncRNA-MALAT1 exerts a functional role in the cancer development as well as the drug resistance and is linked with STAT3 activation and activity of FUT4. Moreover, STAT3-mediated induction of P-GP is well-documented. Natural compounds of Sesquiterpene Lactone (SL) family are well-known for their anticancer properties with particular emphasis over STAT3 inhibitory capabilities. In this study, we explored the positive correlation of MALAT1 with STAT3 and FUT4 activity in paclitaxel resistant A549 (A549/T) lung cancer cells. Additionally, we investigated the anticancer activity of two well-known members of SLs, alantolactone (ALT) and Brevilin A (Brv-A), in A549/T lung cancer cells. ALT and Brv-A induced apoptosis in A549/T cells. Furthermore, these two natural SLs suppressed MALAT1 expression, STAT3 activation, and FUT4 and P-GP expression which are the hallmarks for paclitaxel resistance in A549 lung cancer cells. The inhibition of MALAT1 enhanced the competence of these SLs members significantly, which accounted for the growth inhibition as well as anti-migratory and anti-invasive effects of ALT and Brv-A. These findings suggest SLs to be the promising agents for overcoming paclitaxel resistance in A549 lung cancer cells.

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“…How HE4 and Pac by themselves or in combination may affect cell apoptosis was not addressed in the current study. Thirdly, previous studies have shown an important role of P-gp-mediated multi-drug resistance mechanism for cell response to paclitaxel [40,41]. Although in preliminary experiments we explored the expression changes of several multi-drug resistance genes and did not detect significant alterations, their involvement could not be excluded.…”

Section: Discussionmentioning

confidence: 92%

HE4 overexpression decreases pancreatic cancer Capan-1 cell sensitivity to paclitaxel via cell cycle regulation

Guo

et al. 2020

Cancer Cell Int

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Background: Paclitaxel is a first-line chemotherapy drug for pancreatic, ovarian, endometrial cancers and other malignancies. However, its efficacy is often compromised by decreased cell sensitivity or the development of resistance. Human epididymis protein 4 (HE4) is highly expressed in gynecologic and pancreatic cancer tissues, and its serum levels are used for patient triage and assistant diagnosis of gynecologic cancers. Previous studies have shown that HE4 overexpression could promote cancer cell proliferation and the growth of tumor xenografts, which suggests its potential involvement in cancer chemosensitivity. Methods: Two pancreatic cancer cell lines, Capan-1 and Suit-2, were transiently transfected with an HE4 overexpression plasmid, and transfected cells were treated with paclitaxel. S-phase cells were labeled using BrdU, and cell positivity rates were determined by counting BrdU-positive cells. Following HE4 overexpression and/or drug treatment, a western blotting analysis was performed to determine the protein alterations of PCNA and p21, two important cell cycle regulators. Results: HE4 overexpression not only promoted the proliferation of the Capan-1 pancreatic cells, but also significantly decreased cell sensitivity to paclitaxel. Results from western blotting showed that paclitaxel inhibited cell proliferation by decreasing the expression of PCNA and increasing the expression of p21. Data analysis indicated interactive actions between HE4 function and paclitaxel effects, both converging to cell cycle regulation. Conclusion: These findings suggest that HE4 could be a potential therapeutic target for the sensitization of pancreatic cancer cells to paclitaxel treatment. HE4 expression levels may be used to predict the sensitivity of pancreatic cancer patients to paclitaxel.

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Overcoming Taxol-resistance in A549 cells: A comprehensive strategy of targeting P-gp transporter, AKT/ERK pathways, and cytochrome P450 enzyme CYP1B1 by 4-hydroxyemodin

Cited by 31 publications

References 66 publications

Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

Sesquiterpene Lactones Attenuate Paclitaxel Resistance Via Inhibiting MALAT1/STAT3/ FUT4 Axis and P-Glycoprotein Transporters in Lung Cancer Cells

HE4 overexpression decreases pancreatic cancer Capan-1 cell sensitivity to paclitaxel via cell cycle regulation

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