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miRNAs as short non-coding RNAs in regulating doxorubicin resistance
Sepideh Mirzaei1,2, Mahshid Deldar Abad Paskeh2,3, Farhad Adhami Moghadam4
1Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
Abstract:
The treatment of cancer patients has been prohibited by chemoresistance. Doxorubicin (DOX) is an anti-tumor compound disrupting proliferation and triggering cell cycle arrest via inhibiting activity of topoisomerase I and II. miRNAs are endogenous RNAs localized in cytoplasm to reduce gene level. Abnormal expression of miRNAs changes DOX cytotoxicity. Overexpression of tumor-promoting miRNAs induces DOX resistance, while tumor-suppressor miRNAs inhibit DOX resistance. The miRNA-mediated regulation of cell death and hallmarks of cancer can affect response to DOX chemotherapy in tumor cells. The transporters such as P-glycoprotein are regulated by miRNAs in DOX chemotherapy. Upstream mediators including lncRNAs and circRNAs target miRNAs in affecting capacity of DOX. The response to DOX chemotherapy can be facilitated after administration of agents that are mostly phytochemicals including curcumol, honokiol and ursolic acid. These agents can regulate miRNA expression increasing DOX's cytotoxicity. Since delivery of DOX alone or in combination with other drugs and genes can cause synergistic impact, the nanoparticles have been introduced for drug sensitivity. The non-coding RNAs determine the response of tumor cells to doxorubicin chemotherapy. microRNAs play a key role in this case and they can be sponged by lncRNAs and circRNAs, showing interaction among non-coding RNAs in the regulation of doxorubicin sensitivity.
Insights
Chemoresistance hinders cancer treatment. Non-coding RNAs, particularly microRNAs (miRNAs), significantly influence doxorubicin (DOX) chemotherapy effectiveness by regulating gene expression and drug transporters, impacting patient outcomes.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- Chemoresistance is a major obstacle in cancer therapy, limiting the efficacy of drugs like doxorubicin (DOX).
- Doxorubicin (DOX) is a crucial chemotherapeutic agent that inhibits topoisomerase enzymes, inducing cancer cell death.
- MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally and are implicated in drug resistance.
Purpose of the Study:
- To elucidate the role of non-coding RNAs, especially miRNAs, in modulating doxorubicin (DOX) sensitivity in cancer cells.
- To explore how upstream non-coding RNAs like lncRNAs and circRNAs interact with miRNAs to influence DOX efficacy.
- To investigate the potential of phytochemicals and nanoparticles in overcoming DOX resistance by targeting non-coding RNA pathways.
Main Methods:
- Analysis of miRNA expression profiles in relation to DOX cytotoxicity.
- Investigation of miRNA-mediated regulation of cancer hallmarks and drug transporters (e.g., P-glycoprotein).
- Examination of interactions between miRNAs, lncRNAs, and circRNAs in the context of DOX chemotherapy.
- Evaluation of phytochemicals (curcumol, honokiol, ursolic acid) and nanoparticle delivery systems for enhancing DOX sensitivity.
Main Results:
- Abnormal miRNA expression significantly alters DOX cytotoxicity, with tumor-promoting miRNAs inducing resistance and tumor-suppressor miRNAs inhibiting it.
- miRNAs regulate key cellular processes, including cell death and cancer hallmarks, thereby affecting response to DOX.
- lncRNAs and circRNAs act as upstream regulators, sponging miRNAs and influencing the cellular capacity to handle DOX.
- Phytochemicals demonstrate potential to increase DOX cytotoxicity by modulating miRNA expression.
- Nanoparticle-based delivery systems show promise for improving DOX sensitivity through synergistic drug combinations.
Conclusions:
- Non-coding RNAs, particularly miRNAs, are critical determinants of tumor cell response to doxorubicin chemotherapy.
- The intricate interplay between miRNAs, lncRNAs, and circRNAs offers novel therapeutic targets for overcoming chemoresistance.
- Targeting non-coding RNA pathways with agents like phytochemicals or advanced delivery systems may restore or enhance DOX efficacy in cancer treatment.
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