A1. Differential sensitivities of the cardiac (NCX1.1) and vascular (NCX1.3) isoforms of the NA+-CA2+ exchanger to fatty acids

Ander, Bradley P.; Hurtado, Cecilia; Raposo, Carla S.; Hryshko, Larry V.; Pierce, Grant N.; Lukas, Anton

doi:10.1016/j.yjmcc.2006.03.283

Cited by 1 publication

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“…We filtered out 47 drugs (inhibitors) whose targets involve Doxo associated calcium channels and pumps present in our model namely, IP 3 R2, SERCA1, VGCC, ORAI1, TRPC1, and NCX. We also did the literature survey and found inhibitors of calcium channels and pumps present in our study [54][55][56]. A complete list of drugs, drug targets, and associated parameters of our model used for further analysis is given in the Supplementary Table . We defined two cases Doxo 3 and Doxo 3 + drug in which the associated parameter with the drug is reduced by 50%.…”

Section: Parameter Recalibrationmentioning

confidence: 99%

Understanding doxorubicin associated calcium remodeling during triple-negative breast cancer treatment: an in silico study

Arora

Ghosh

Chatterjee

2021

Exploration of Targeted Anti-Tumor Therapy

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Aim: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with high heterogeneity, rapid progression, and paucity of treatment options. The most effective chemotherapeutic drug used to treat TNBC is doxorubicin (Doxo) which is an anthracycline antibiotic. However, Doxo treatment alters cytosolic calcium dynamics leading to drug-resistance condition. The aim of this study is to capture the alterations in the activity of various calcium channels and pumps during Doxo treatment and their consequences on cytosolic calcium dynamics that ultimately result in drug resistance. Methods: In the present study, a mathematical model is proposed to capture the complex dynamical landscape of intracellular calcium during Doxo treatment. This study provides an insight into Doxo remodeling of calcium dynamics and associated drug-resistance effect. The model was first analyzed analytically and then explored through numerical simulation using techniques like global sensitivity analysis, parameter recalibration, etc. Results: The model is used to predict the potential combination therapy for Doxo that can overcome Doxo associated drug resistance. The results show targeting the dysregulated Ca2+ channels and pumps might provide efficient chemotherapy in TNBC. It was also observed that the indispensability of calcium influx rate is paramount in the Doxo drug resistance. Finally, three drugs were identified from existing literature that could be used as a combination therapy along with Doxo. Conclusions: The investigation highlights the importance of integrating the calcium signaling of various calcium regulating compounds for their effective anti-tumor effects deliverance along with chemotherapeutic agents. The results from this study might provide a new direction to the experimental biologists to explore different combination therapies with Doxo to enhance its anti-tumor effect.

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Section: Parameter Recalibrationmentioning

confidence: 99%