Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death

Kopecka, Joanna; Godel, Martina; Dei, Silvia; Giampietro, Roberta; Belisario, Dimas Carolina; Akman, Muhlis; Contino, Marialessandra; Teodori, Elisabetta; Riganti, Chiara

doi:10.3390/cells9041033

Cited by 24 publications

(20 citation statements)

References 46 publications

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“…In overcoming P-glycoprotein (P-gp)-expressing doxorubicin resistance in breast cancer cells, the clinically approved P-gp inhibitor tariquidar and its derivatives restored doxorubicin accumulation and enhanced ICD, defined as an increase in CRT translocation and the release of HMGB1 and ATP [ 94 ]. Thus, pharmacological compounds that abolish drug resistance may act as chemosensitizers and immunosensitizers, increasing the therapeutic effect.…”

Section: Roles Of Damps and Icd In The Clinical Significance Of Breast Cancermentioning

confidence: 99%

Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer

Kim¹,

Kin

2021

Cancers

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How primary breast cancer can be cured after (neo)adjuvant therapy remains unclear at the molecular level. Immune activation by anticancer agents may contribute to residual tumor cell eradication with postsurgical (neo)adjuvant chemotherapy. Chemotherapy-induced immunogenic cell death (ICD) may result in long-term immune activation with memory effector T cells, leading to a primary breast cancer cure. Anthracycline and taxane treatments cause ICD and immunogenic modulations, resulting in the activation of antitumor immunity through damage-associated molecular patterns (DAMPs), such as adenosine triphosphate, calreticulin, high mobility group box 1, heat shock proteins 70/90, and annexin A1. This response may eradicate residual tumor cells after surgical treatment. Although DAMP release is also implicated in tumor progression, metastasis, and drug resistance, thereby representing a double-edged sword, robust immune activation by anticancer agents and the subsequent acquisition of long-term antitumor immune memory can be essential components of the primary breast cancer cure. This review discusses the molecular mechanisms by which anticancer drugs induce ICD and immunogenic modifications for antitumor immunity and targeted anti-DAMP therapy. Our aim was to improve the understanding of how to eradicate residual tumor cells treated with anticancer drugs and cure primary breast cancer by enhancing antitumor immunity with immune checkpoint inhibitors and vaccines.

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Section: Roles Of Damps and Icd In The Clinical Significance Of Breast Cancermentioning

confidence: 99%

Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer

Kim¹,

Kin

2021

Cancers

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“…The difference of doxorubicin concentration between the two series, expressed as nmol doxorubicin extruded/min/mg cell protein was plotted versus the initial drugs’ concentration. Values were fitted to Michaelis‐Menten equation to calculate Vmax and Km, using the Enzfitter software (Biosoft Corporation, Cambridge, United Kingdom) [47] …”

Section: Methodsmentioning

confidence: 99%

Overcoming Multidrug Resistance (MDR): Design, Biological Evaluation and Molecular Modelling Studies of 2,4‐Substituted Quinazoline Derivatives

et al. 2022

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Some 2,4-disubstituted quinazolines were synthesized and studied as multidrug resistance (MDR) reversers. The new derivatives carried the quinazoline-4-amine scaffold found in modulators of the ABC transporters involved in MDR, as the TKIs gefitinib and erlotinib. Their behaviour on the three ABC transporters, P-gp, MRP1 and BCRP, was investigated. Almost all compounds inhibited the P-gp activity in MDCK-MDR1 cells overexpressing P-gp, showing EC 50 values in the nanomolar range (1 d, 1 e, 2 a, 2 c, 2 e). Some compounds were active also towards MRP1 and/or BCRP. Docking results obtained by in silico studies on the P-gp crystal structure highlighted common features for the most potent compounds. The P-gp selective compound 1 e was able to increase the doxorubicin uptake in HT29/DX cells and to restore its antineoplastic activity in resistant cancer cells in the same extent of sensitive cells. Compound 2 a displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP.

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“…The past three generations of p-gp inhibitors/modulators have not proven to be very successful due to low therapeutic index, presumably because of expression in several tissue types. However, a recent study has shown that inhibitors reducing both the amount and activity of p-gp are effective chemo-immmunesensitising agents ( Kopecka et al, 2020 ). P-gp also has similar effects on drug concentration within the brain.…”

Section: Transportersmentioning

confidence: 99%

Cell Surface Transporters and Novel Drug Developments

Carmichael

Day

2022

Front. Pharmacol.

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Despite the numerous scientific and technological advances made within the last decade the attrition rates for new drug discovery remain as high as 95% for anticancer drugs. Recent drug development has been in part guided by Lipinski’s Rule of 5 (Ro5) even though many approved drugs do not comply to these rules. With Covid-19 vaccine development strategy dramatically accelerating drug development perhaps it is timely to question the generic drug development process itself to find a more efficient, cost effective, and successful approach. It is widely believed that drugs permeate cells via two methods: phospholipid bilayer diffusion and carrier mediated transporters. However, emerging evidence suggests that carrier mediated transport may be the primary mechanism of drug uptake and not diffusion as long believed. Computational biology increasingly assists drug design to achieve desirable absorption, distribution, metabolism, elimination and toxicity (ADMET) properties. Perfecting drug entry into target cells as a prerequisite to intracellular drug action is a logical and compelling route and is expected to reduce drug attrition rates, particularly gaining favour amongst chronic lifelong therapeutics. Novel drug development is rapidly expanding from the utilisation of beyond the rule of five (bRo5) to pulsatile drug delivery systems and fragment based drug design. Utilising transporters as drug targets and advocating bRo5 molecules may be the solution to increasing drug specificity, reducing dosage and toxicity and thus revolutionising drug development. This review explores the development of cell surface transporter exploitation in drug development and the relationship with improved therapeutic index.

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Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death

Cited by 24 publications

References 46 publications

Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer

Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer

Overcoming Multidrug Resistance (MDR): Design, Biological Evaluation and Molecular Modelling Studies of 2,4‐Substituted Quinazoline Derivatives

Cell Surface Transporters and Novel Drug Developments

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