Drug metabolizing enzymes and their inhibitors' role in cancer resistance

Pathania, Shelly; Bhatia, Rohit; Baldi, Ashish; Singh, Randhir; Rawal, Ravindra K.

doi:10.1016/j.biopha.2018.05.117

Cited by 90 publications

(66 citation statements)

References 80 publications

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“…To date, the most viable targeting approaches are enzyme inhibition (Griffith et al, 2010;Pathania et al, 2018;Scatena et al, 2008), which yielded several FDA-approved anti-cancer drugs, and protein-protein interaction (PPI) disruption, which yielded several compounds with great therapeutic promise (Ivanov et al, 2013). However, drugs directly targeting disordered regions are still lacking.…”

Section: Targeting Strategies Can Be Developed For Disordered Driversmentioning

confidence: 99%

“…The identification of functional modules that are directly altered in cancer driver genes can serve with potential targets for pharmaceutical intervention. Most current anticancer drugs are inhibitors designed against enzyme activity (using either competitive or noncompetitive inhibition) (Griffith et al, 2010;Pathania et al, 2018;Scatena et al, 2008). In general, currently successful drug development efforts mainly focus on ordered protein domains, in the framework of structurebased rational drug design (Lounnas et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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How mutations of intrinsically disordered protein regions can drive cancer

Mészáros

Hajdu-Soltész

Zeke

et al. 2020

Preprint

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Intrinsically disordered regions (IDRs) are important functional modules of several proteins, providing extra layers of regulation as switchable structural elements. Protein disorder has been associated with cancer, but it is unknown whether IDR mutations represent a distinct class of driver events associated with specific molecular mechanisms and system level properties, which would require dedicated targeting strategies. Based on an integrative computational approach, we identified 47 IDRs whose genetic mutations can be directly linked to cancer development. While not as common as alterations of globular domains, IDR mutations contribute to the emergence of the same cancer hallmarks through the modulation of distinct molecular mechanisms, increased interaction potential and specific functional repertoire. We demonstrate that in specific cancer subtypes, IDR mutations represent the key events driving tumorigenesis. However, treatment options for such patients are currently severely limited. We suggest targeting strategies that could enable successful therapeutic intervention for this subclass of cancer drivers, extending our options for personalized therapies.

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Section: Targeting Strategies Can Be Developed For Disordered Driversmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

How mutations of intrinsically disordered protein regions can drive cancer

Mészáros

Hajdu-Soltész

Zeke

et al. 2020

Preprint

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“…Metabolism of xenobiotics, as well as anticancer drugs, occurs in several stages and includes several enzymes and membrane transporters for the drug export from the human cells (PATHANIA et al, 2018). Their crucial and primary role is to protect healthy cells against harmful effects of carcinogens.…”

Section: Effects On Gene Expression Of Biotransformation Enzymes and mentioning

confidence: 99%

“…Related to this field of investigation, T. chamaedrys shows high potential to alternate expression of GSTP1 and MRP-2. This is an important result considering the need for investigation of some chemo-modulators, GST and ABC transporters inhibitors, as therapeutic agents in order to reverse drug resistance (ZHAO et al, 2007;PATHANIA et al, 2018).…”

Section: Effects On Gene Expression Of Biotransformation Enzymes and mentioning

confidence: 99%

Altered apoptosis and biotransformation signaling in HCT-116 colorectal carcinoma cells induced by Teucrium chamaedrys L. extract

Milutinovic¹,

Nikodijević²,

Stanković³

et al. 2019

Kragujevac J Science

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The aim of this study was an investigation of pro-apoptotic activity of methanol extract from T. chamaedrys, a more detailed determination of the signal molecules activated in the process of apoptosis, and effects on mRNA expression of enzymes involved in biotransformation (CYP1A1 and GSTP1) and membrane transporter, MRP-2 in HCT-116 colorectal carcinoma cells. The results show pronounced proapoptotic activity of T. chamaedrys extract, due to activation of both extrinsic and intrinsic pathways. The death receptor associated signaling pathway was activated in HCT-116 following treatment by T. chamaedrys, via increased Fas receptor expression and activity of caspase 8. Activation of caspase 9 suggests that mitochondrial signalling also has an impact. The extract reduced mRNA expression of GSTP1 and MRP-2 genes, as one of the causes of multi drug resistance in cancer cells. Observed results offer the possibility for the use of T. chamaedrys extract in the context of cancer prevention and therapy.

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“…Despite initial treatment response, cancer cells can eventually develop resistance, which can result from the acquisition of intrinsic characteristics of cancer cells, and the action of extrinsic factors. Such intrinsic cancer cell characteristics include genetic alterations (mutations, amplifications, deletions, translocations) and epigenetic modifications (methylation, acetylation) that can determine the aberrant expression of genes controlling drug metabolism (inactivation, efflux, target modification), cancer cell survival (inhibition of cell death, pro-survival signaling), or the acquisition of cancer stem cell phenotypes [1][2][3][4][5][6][7][8][9] . Extrinsic factors include the activation of signaling pathways in the tumor microenvironment (TME) that drive the acquisition of drug resistance in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Gut microbiota: a new player in regulating immune- and chemo-therapy efficacy

Anfossi

Calin

2020

CDR

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Development of drug resistance represents the major cause of cancer therapy failure, determines disease progression and results in poor prognosis for cancer patients. Different mechanisms are responsible for drug resistance. Intrinsic genetic modifications of cancer cells induce the alteration of expression of gene controlling specific pathways that regulate drug resistance: drug transport and metabolism; alteration of drug targets; DNA damage repair; and deregulation of apoptosis, autophagy, and pro-survival signaling. On the other hand, a complex signaling network among the entire cell component characterizes tumor microenvironment and regulates the pathways involved in the development of drug resistance. Gut microbiota represents a new player in the regulation of a patient's response to cancer therapies, including chemotherapy and immunotherapy. In particular, commensal bacteria can regulate the efficacy of immune checkpoint inhibitor therapy by modulating the activation of immune responses to cancer. Commensal bacteria can also regulate the efficacy of chemotherapeutic drugs, such as oxaliplatin, gemcitabine, and cyclophosphamide. Recently, it has been shown that such bacteria can produce extracellular vesicles (EVs) that can mediate intercellular communication with human host cells. Indeed, bacterial EVs carry RNA molecules with gene expression regulatory ability that can be delivered to recipient cells of the host and potentially regulate the expression of genes involved in controlling the resistance to cancer therapy. On the other hand, host cells can also deliver human EVs to commensal bacteria and similarly, regulate gene expression. EVmediated intercellular communication between commensal bacteria and host cells may thus represent a novel research area into potential mechanisms regulating the efficacy of cancer therapy.

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Drug metabolizing enzymes and their inhibitors' role in cancer resistance

Cited by 90 publications

References 80 publications

How mutations of intrinsically disordered protein regions can drive cancer

How mutations of intrinsically disordered protein regions can drive cancer

Altered apoptosis and biotransformation signaling in HCT-116 colorectal carcinoma cells induced by Teucrium chamaedrys L. extract

Gut microbiota: a new player in regulating immune- and chemo-therapy efficacy

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