miRNAs as short non-coding RNAs in regulating doxorubicin resistance

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.

Graphical abstract

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.

Introduction

As an anthracycline antidiabetic, doxorubicin (DOX) is widely employed in the therapy of cancer (Meredith and Dass 2016; Tran et al. 2021; Sohail et al. 2021). DOX is derived from Streptomyces peucetius species and owing to its pleiotropic function, it is deployed for treatment of various cancers (Minotti et al. 2004; Keizer et al. 1990). Based on the studies, DOX application in therapy of various tumors such as breast cancer (Batist et al. 2002), lung cancer (Farago et al. 2019), acute leukemia (Ruggiero et al. 2013), childhood solid tumors (Marina et al. 2002), lymphoma (Guo et al. 2011), and soft tissue sarcomas (Carvalho et al. 2009). One of the most important drawbacks of DOX is its non-selectivity and affecting normal cells. The optimal doses of DOX in treatment of cancer patients should be deployed to prevent unexpected effects after chemotherapy (Mirzaei et al. 2023). The reason for toxicity of DOX on normal cells is related to increasing ROS levels and mediating mitochondrial damage. However, adverse impacts on organs and tissues are not the only problem faced in DOX chemotherapy. It has been shown that tumor cells have capacity of developing DOX resistance upon frequent application of this anti-cancer agent (Lovitt et al. 2018; Kang et al. 2017; Wen et al. 2019; Zhang et al. 2021a).

Upon intravenous injection, DOX demonstrates multiphasic deposition in various organs of body. After that, DOX undergoes a triphasic plasma clearance (Tacar et al. 2013). The distribution half-life of DOX is suggested to be 3–5 min, demonstrating that DOX undergoes rapid absorption by the cells. The terminal half-life of DOX is suggested to be 24–36 h and it demonstrates that elimination of DOX from body takes longer than its uptake by cells (Zheng et al. 2006). DNA-associated enzymes including topoisomerase I and II are suppressed by DOX through DNA intercalation. At the next step, DOX evokes cell cycle arrest, suppresses proliferation and mediates DNA damage (Tacar et al. 2013; Hilmer et al. 2004; Buchholz et al. 2002). After DNA damage, tumor cells try to repair it and if they fail, apoptosis occurs. Furthermore, anti-proliferative activity of DOX is related to suppressing at G1 and G2 phases. Plus to inhibiting activities of topoisomerase I and II, DOX itself binds to DNA and by inhibiting DNA and RNA polymerases, it prevents DNA replication and RNA transcription (Tacar et al. 2013).

Tumor cells switch among various signaling networks in increasing their progression and inducing resistance to therapy (Hong et al. 2019; Gao et al. 2020a). Overexpression of STAT5a evokes DOX resistance in breast tumor cells through ABCB1 upregulation (Li et al. 2021a). The differentiation rate of neuroblastoma cells undergoes a significant decrease by Wnt signaling inhibition and after that, DOX sensitivity is obtained (Suebsoonthron et al. 2017). A combination of STAT3, β-catenin and Notch-1 signaling participates in mediating DOX resistance. siRNA reducing expression of STAT3, β-catenin and Notch-1 enhances DOX sensitivity (Alshaer et al. 2019). TMEPAI undergoes activation by TGF-β to elevate activity of drug transporters and to evoke EMT in DOX resistance (Wardhani et al. 2021). A combination of apigenin and DOX increases PTEN expression and inhibits PI3K/Akt in facilitating DOX sensitivity of prostate tumor (Ayyildiz et al. 2021). Curcumin-mediated P-gp suppression also promotes DOX sensitivity (Zhang et al. 2021a). Overexpression of P-gp leads to DOX resistance and its inhibition by therapeutics is recommended such as nanostructures (Mirzaei et al. 2022). The dysregulation of miRNAs also contributes to the DOX resistance (Zangouei et al. 2021). The current review provides an analysis of miRNA function in regulation of DOX resistance in different human cancers. After discussing the biogenesis of miRNAs and their function in cancer progression, this review specifically describes the role of miRNAs in modulation cancer proliferation and metastasis to relate them with response to DOX chemotherapy. Moreover, two distinct categories of miRNAs including tumor-promoting and tumor-suppressor miRNAs in induction and inhibition of DOX resistance, respectivey are discussed. Then, the regulation of miRNAs by other nan-coding RNA molecules is brought into attention. The impact of anti-cancer compounds such as ursolic acid and honokiol in regulation of DOX response and miRNAs is discussed. Finally, the delivery of DOX by nanocarriers and also, providing synergistic cancer therapy by delivery of genes or other drugs in overcoming chemoresistance or combination therapy is discussed.

miRNAs: biogenesis and carcinogenesis regulation

Biogenesis

The ncRNAs are evolutionary conserved RNA molecules that are not transcribed into proteins and they could control multiple biological events (Indrieri et al. 2020; Kalfert et al. 2020; Li et al. 2021b). miRNAs are endogenous short non-coding RNA molecules that their length is at the range of 18–22 nucleotides. The gene expression regulation is performed by miRNAs and most of them are involved in reducing expression level of target gene. This activity is mediated by binding to special regions in messenger RNA (mRNA) known as 3′-UTR to prevent translation or mediate degradation (Manvati et al. 2020; Korać et al. 2021; Zanoaga et al. 2021). The biogenesis of miRNAs is a multistep process occurring in both nucleus and cytoplasm. The mature and functional miRNAs capable of regulating gene expression are finally produced in cytoplasm. The RNA polymerase I or II participate in generating primary miRNA (pri-miRNA) and then, DGCR8 starts its function in producing precursor miRNA (pre-miRNA) from pri-miRNA. Then, the condition is provided for transferring pre-miRNA into cytoplasm with the help of exportin-5-Ran-GTP complex to produce a mature miRNA, to load it into RISC and to generate a functional miRNA (Fig. 1).

Fig. 1.

The biogenesis of miRNAs in cells. RNA polymerase I or II can mediate biogenesis of pri-miRNA in nucleus that undergoes further processing by DGCR8 to generate pre-miRNA. Then, exportin 5 transfers it into cytoplasm to produce mature miRNA and to load it into RISC complex

miRNAs in regulation of carcinogenesis

After the discovery of miRNAs and by advances in field of biology and next generation sequencing, miRNA’s role in diseases and cancer was evaluated (Zhang et al. 2021b; Li et al. 2021c; Tanaka et al. 2021; Xie et al. 2021). It has been shown that miRNA-200c-3p increases growth and invasion of gastric tumor by KLF6 suppression (Wang et al. 2021a). miRNA-199b-5p-induced EMT enhances metastasis by HHIP inhibition (Chen et al. 2021a). miRNA-34a-mediated ZEB1 downregulation impairs melanoma malignancy (Xu et al. 2021). The miRNAs packed in exosomes are diagnostic markers. miRNA-187 is found in exosomes derived from plasma of hepatocellular carcinoma patients and has a poor expression, while miRNA-509-3p demonstrates an increase in expression. miRNA-187 down-regulation and miRNA-509-3p overexpression mediate undesirable prognosis (Dai et al. 2021). Exosomal miRNA-4443 stimulates cisplatin resistance in lung tumor through ferroptosis inhibition (Song et al. 2021a). miRNA-149-3p-mediated cisplatin insensitivity in ovarian tumor is performed by TIMP2 and CDCN1A downregulation (Wang et al. 2021b). There are also upstream regulators of miRNAs in cancer. For instance, LINC00922 sponges miRNA-361-3p to mediate EMT (Lu et al. 2021a). CircNUP98 prevents maturation of miRNA-519a-3p and it is localized in both nucleus and cytoplasm. CircNUP98 reduces mice survival and increases tumor proliferation in glioblastoma (Lu et al. 2021a). There are also anti-cancer agents targeting miRNAs in tumor suppression. Curcumin-mediated miR-320a downregulation via circ-PLEKHM3 overexpression could impair proliferation and induce apoptosis in ovarian cancer (Sun and Fang 2021). These evidences reveal the importance of miRNAs in cancer therapy and their association with various signaling networks. They affect proliferation, invasion and therapy response. Plus to revealing the role of miRNAs in drug resistance, the detection methods for miRNAs have been also introduced (Hu et al. 2022).

Upstream regulators of miRNAs in doxorubicin chemotherapy

LncRNAs regulating miRNAs in doxorubicin chemotherapy

One of the subclasses of non-protein coding RNAs is lncRNAs that demonstrate size higher than 200 nts and control biological mechanisms such as proliferation, autophagy, apoptosis and differentiation (Hashemi et al. 2022). The transcription of lncRNAs is conducted by RNA polymerase II and they lack protein coding potential (Kanojia et al. 2022). The lncRNAs are categorized based on genomic locations and their function depends on the location in nucleus or cytoplasm (Shabna et al. 2023). The lncRNAs could for tumor diagnosis and they can modulate chemoresistance (Pandya et al. 2020). The gene expression at transcriptional, post-transcriptional and epigenetic levels is regulated by lncRNAs and abnormal expression of these RNA molecules leads to development of various cancers (Wu et al. 2018; Schmitt and Chang 2016). LncRNAs affect miRNA expression and reduce its expression via sponging. LINC01977-mediated miR-212-3p sponging promotes GOLM1 levels to induce DOX resistance (Li et al. 2021d). Notably, a certain lncRNA can participate in resistance to two chemotherapeutic agents. miRNA-217 overexpression impairs gastric tumor. HOTAIR downregulates miRNA-217 to increase growth and invasion of gastric tumor, leading to paclitaxel and DOX resistance (Wang et al. 2018). Silencing TUG1 promotes DOX sensitivity of breast cancer and causes apoptosis. LncRNA TUG1 induces DOX resistance in breast tumor via miRNA-9 disruption (Wang et al. 2020a). miRNA-200c-3p downregulates ANLN to increase DOX sensitivity. Silencing XIST stimulates proliferation inhibition and mediates apoptosis in breast cancer. LncRNA XIST sponges miRNA-200c-3p to overexpress ANLN in DOX resistance (Zhang et al. 2020a).

CircRNAs regulating miRNAs in doxorubicin chemotherapy

circRNAs are RNAs with a special structure that lack 5/caps and 3′ poly-A tails and they are involved in important biological mechanisms in cells (Guarnerio et al. 2016; Wang et al. 2019a). The dysregulation of circRNAs could causes pathologies, more evident in carcinogenesis (Yin et al. 2021; Wu et al. 2021; Shi et al. 2021a). CircRNAs are able to exert their function via regulating expression of miRNAs. CircCSPP1 promotes DOX resistance in colorectal cancer. Silencing circCSPP1 impairs progression of colorectal cancer and induces apoptosis. CircCSPP1 dpeletion mediates DOX sensitivity in colorectal cancer. Levels of circCSPP1 and FZD7 increases in colorectal cancer, while miRNA-944 as tumor-suppressor factor downs downregulation. CircCSPP1 decreases expression level of miRNA-944 to elevate FZD7 level, causing DOX resistance (Yi et al. 2021). Exposing cancer to DOX can increase expression level of circRNAs involved in drug resistance. Expression level of circRNA-0004674 increases in osteosarcoma cells upon exposure to DOX. It has been shown that DOX-mediated increase in circRNA-0004674 expression downregulates miRNA-142-5p to promote MCL1 expression, resulting in DOX resistance. Restoring miRNA-142-5p expression or silencing circRNA-0004674 can lead to DOX sensitivity in osteosarcoma (Ma et al. 2021). Such strategy has been used in a recent experiment. CircRNA VANGL1 accelerates tumorigenesis in bladder tumor. VANGL1 overexpression prevents apoptosis and induces DOX resistance in bladder cancer cells. VANGL1 sponges miRNA-145-5p to upregulate SOX4, resulting in DOX resistance in bladder cancer (Zhu and Zhang 2021). CircITCH conducts a tumor-suppressor function in osteosarcoma. Level of circITCH diminishes in osteosarcoma to cause DOX resistance. Restoring circITCH expression stimulates apoptosis in osteosarcoma and decreases growth and invasion. CircITCH sponges miRNA-524 to facilitate RASSF6 in DOX sensitivity (Zhou et al. 2021).

The exosomes can be considered as nanocarriers to deliver the cargo in disease therapy (Gorshkov et al. 2022; Rajput et al. 2022). The intracellular communication is provided by exosomes and they are absorbed by target cells to exert their function (Meldolesi 2018). Exosomes are able to transfer genetic materials among cells and circRNAs are among them (Shi et al. 2020). Exosomal circPRRX1 evokes DOX insensitivity in gastric cancer. Silencing circPRRX1 impairs gastric tumor in developing DOX insensitivity. Exosomal circPRRX1 sponges miRNA-3064-5p to facilitate PTPN14 levels, causing DOX resistance (Wang et al. 2020b).

miRNA-663 is a tumor-promoting factor in gastric cancer that reduces expression of FADD to prevent apoptosis and to mediate DOX resistance. It has been shown that miRNA-663 has binding sites for Foxo3a and Foxo3a reduces expression of miRNA-663 to promote FADD expression, resulting in an increase in DOX-mediated apoptosis in gastric cancer cells (Pang et al. 2019). Taking everything together, it appears that miRNAs are key players in DOX cytotoxicity on tumor cells and their regulation by other factors can complicate signaling networks involved in this process (Fig. 2) (Zhou et al. 2021; Zhou et al. 2018a; Wang et al. 2020b; Wang et al. 2021c; Pang et al. 2019; Zeng et al. 2020; Cao et al. 2021; Ji 2020). Table 1 provides a summary of miRNA regulation in DOX chemotherapy.

Fig. 2.

Regulation of miRNAs in chemotherapy. LncRNAs and circRNAs with other transcription factors such as Foxo3a can regulate miRNAs in DOX chemotherapy

Table 1.

The regulation of miRNAs by upstream mediators in DOX chemotherapy

miRNA	Signaling network	Cancer type	Remarks	References
LINC01977	miRNA-212-3p/GOLM1	Breast cancer	Overexpression of LINC01977 in breast tumor cells Association with tumor progression and drug resistance miRNA-212-3p down-regulation by LINC01977 to increase GOLM1 expression	Li et al. (2021d)
HOTAIR	miRNA-217/PTPN14 miRNA-217/GPC5	Gastric cancer	Induction of paclitaxel and DOX resistance in cancer cells miRNA-217 inhibition by HOTAIR Upregulation of PTPN14 and GPC5 Increasing tumor progression	Wang et al. (2018)
TBX15	miRNA-152/KIF2C	Breast cancer	TBX15 promotes miRNA-152 expression to increase DOX sensitivity of tumor cells Inhibition of autophagy and glycolysis Reducing expression level of KIF2C	Jiang et al. (2021)
TUG1	miRNA-9-5p/eIF5A2	Breast cancer	miRNA-9-5p down-regulation by TUG1 Increasing expression level of eIF5A2 to mediate DOX resistance in cancer cells	Wang et al. (2020a)
XIST	miRNA-200c-3p/ANLN	Breast cancer	miRNA-200c-3p down-regulation by XIST leads to ANLN overexpression Increasing progression of tumor cells and triggering DOX resistance	Zhang et al. (2020a)
CircCSPP1	miRNA-944/FZD7	Colorectal cancer	CircCSPP1 promotes FZD7 expression to mediate miRNA-944 down-regulation, resulting in DOX resistance in cancer cells	Yi et al. (2021)
CircRNA-0004674	miRNA-142-5p/MCL1	Osteosarcoma	DOX treatment promotes expression level of circRNA-0004674 leads to upregulation of MCL1 via miRNA-142-5p inhibition	Ma et al. (2021)
VANGL1	miRNA-145-5p/SOX4	Bladder cancer	VANGL1 promotes SOX4 expression via miRNA-145-5p sponging Apoptosis inhibition Increased proliferation and viability of tumor cells Mediating DOX resistance	Zhu and Zhang (2021)

miRNA-mediated proliferation regulation and doxorubicin chemotherapy

miRNAs, PTEN, PI3K/Akt and IGF-1R

The capacity of cancer cells for abnormal growth causes a problem to decrease population. There is a close connection between proliferation rate and drug resistance. Growth disruption enhances chemosensitivity. In respect to the effect of miRNAs on biological mechanisms in cells that proliferation is one of them, miRNAs are capable of affecting chemotherapy response via regulating growth of tumor cells. PI3K/Akt is a tumor-promoting pathway that its induction causes growth and invasion acceleration. PTEN is upstream regulators of PI3K/Akt and diminishes formation of PI3K to interfere this pathway (Wise et al. 2017; Papa and Pandolfi 2019). miRNA-202-5p demonstrates high expression in breast tumor, while expression level of PTEN reduces. Restoring miRNA-202-5p expression induces DOX insensitivity and accelerates proliferation of breast cancer. Furthermore, miRNA-202-5p upregulation reduces apoptosis in breast tumor that is of interest for mediating drug resistance. Poor expression of miRNA-202-5p causes DOX sensitivity via growth inhibition and apoptosis induction. In vivo experiment revealed that miRNA-202-5p down-regulation reduces tumor volume. miRNA-202-5p down-regulates PTEN expression to induce PI3K/Akt in increasing proliferation rate of breast tumor and triggering DOX resistance (Liu et al. 2019a). miRNA-520b overexpression can facilitate DOX sensitivity of breast cancer. IGF-1R is involved in increasing carcinogenesis and mediating resistance to apoptosis. miRNA-520b suppresses IGF-1R expression to accelerate apoptosis and elevate DOX sensitivity of breast tumor (Zhang et al. 2021c).

Exosomal miRNAs

Exosomes belong to extracellular vesicles (EVs) and they contain lipid bilayer membranes (Liu et al. 2021). Exosomes are secreted into extracellular matrix and they can contain proteins, lipids and RNAs (Kowal et al. 2014; Sousa et al. 2015; Théry et al. 2002; Ashrafizadeh et al. 2022). In respect to their cargoes, exosomes can influence biological pathways including angiogenesis (Teng et al. 2015), autophagy (Baixauli et al. 2014), and differentiation (Ashrafizadeh et al. 2022; Nair et al. 2014), among others. Therefore, exosomes can carry miRNAs among cells for providing intercellular communication. miRNA-501 can be transferred to gastric tumor through exosomes and it has tumor-promoting function. Exosomal miRNA-501 reduces expression level of BLID to elevate carcinogenesis, to suppress apoptosis and to mediate DOX resistance in gastric cancer cells (Liu et al. 2019b). Exosomes can be secreted by macrophages. Macrophage-derived exosomal miRNA-223 can stimulate DOX insensitivity in gastric cancer. FBXW7 undergoes down-regulation by exosomal miRNA-223 to facilitate DOX resistance (Gao et al. 2020b).

miRNAs, stemness and DNA damage repair

STAT3 elevates stemness of breast cancer and to this end, it promotes expression level of HIF-1. The STAT3/HIF-1 axis is involved in triggering DOX resistance in breast cancer stem cells. miRNA-124 suppresses STAT3/HIF-1 axis in facilitating DOX sensitivity (Liu et al. 2019c). Another important factor is DNA damage repair in cancer cells. Overexpression of PARP1 paves the way for DNA damage repair and mediates DOX insensitivity in lung tumor. miRNA-7-5p can inhibit PARP1 expression to prevent DNA repair, leading to DOX sensitivity in lung cancer (Lai et al. 2019).

miRNAs and autophagy

Proliferation rate, apoptosis and DNA damage were discussed previously and miRNAs regulate them in DOX chemotherapy. One of the most important and challenging mechanisms during DOX chemotherapy is autophagy. Similar to apoptosis, autophagy is a programmed cell death mechanism that causes degradation and recycling of aged and degraded macromolecules and organelles in cells. Primary aim of autophagy is to maintain homeostasis. However, abnormal activation of autophagy occurs in tumor and may cause tumorigenesis, since autophagy exerts dual roles (Ashrafizadeh et al. 2023). In addition, chemotherapy response is influenced by autophagy (Qin et al. 2023). Autophagy reduces DOX response in hepatocellular carcinoma. miRNA-223 shows poor level in DOX-resistant tumor and its upregulation is associated with autophagy inhibition. miRNA-223 reduces FOXO3 expression to impair autophagy, evoking DOX sensitivity of hepatocellular carcinoma (Zhou et al. 2019). miRNA-26b can also inhibit autophagy in facilitating DOX sensitivity of hepatocellular carcinoma and this strategy has been beneficial in vivo for reducing tumor growth (Li et al. 2021d). These two studies highlighted protective role of autophagy and future studies should emphasize on anti-cancer function of autophagy and its induction by miRNAs in increasing DOX sensitivity. Overall, proliferation rate and survival of tumor are tightly controlled by miRNAs in affecting DOX resistance/sensitivity of tumor cells (Fig. 3) (Lin et al. 2020; Zhang et al. 2020b; Hu et al. 2018; Al-Momany et al. 2021).

Fig. 3.

Association of miRNAs regulating tumor growth with DOX resistance/sensitivity. Important biological mechanisms in tumor cells including apoptosis and autophagy are modulated by miRNAs to affect DOX’s response of tumor cells. STAT3, HIF-1 and PTEN are among the signaling networks affected by miRNAs in modulating tumor proliferation

miRNA-mediated metastasis regulation in doxorubicin chemotherapy

General description of metastasis

The tumors can metastasize to neighboring and distant tissues to establish new colonies. The metastasis of tumor cells has resulted in dissemination in body and ensuring survival. Although metastasis remarkably reduces patient survival and mediates undesirable prognosis. It has been shown that increased migration causes drug insensitivity. The miRNA and metastasis in determining DOX response is evaluated here. The EMT-mediated carcinogenesis acceleration can cause chemoresistance.

miRNAs, EMT and doxorubicin chemotherapy

miRNA-451a delays tumorigenesis in lung tumor. miRNA-451a suppresses c-Myc to suppress EMT mechanism, causing DOX sensitivity (Tao et al. 2020). miR-137 is also an inhibitor of EMT, but in breast tumor and accelerator of DOX sensitivity. miRNA-137 downregulates DUSP4 to interfere EMT and disrupt DOX resistance (Du et al. 2019). It has been shown that FBXW7 overexpression increases DOX sensitivity in colorectal tumor cells. miRNA-223 has capacity of downregulating FBXW7 to mediate EMT and to increase metastasis of colorectal cancer cells, resulting in DOX resistance (Ding et al. 2018). miRNA-200b is inhibited in breast cancer, while EMT stimulation occurs to mediate DOX insensitivity. miR-200b-mediated FN1 suppression can increase DOX sensitivity through EMT interference (Yang et al. 2017).

Lung cancer is a threat to human health. It has two subtypes such as SCLC and NSCLC that NSCLC is the malignant one and comprises 85% of cancer cases. The NSCLC cells have demonstrated capacity in developing DOX resistance (Jin et al. 2020). The miRNA-223 and FBW7 association determines DOX response of NSCLC cells. Low expression of FBW7 mediates poor response of NSCLC to DOX. Silencing Twist as upstream mediator of EMT elevates DOX sensitivity. Noteworthy, exposing NSCLC cells to DOX causes EMT via E-cadherin inhibition and vimentin acceleration. miRNA-223 owing to its tumor-promoting function, has capacity of reducing FBW7 levels to augment EMT in NSCLC cells, to facilitate their invasion and to reduce DOX sensitivity (Li et al. 2016).

Challenges and gaps

However, there are some studies showing that both chemo-sensitivity and metastasis can be regulated by miRNAs at a same time, but their association has not been investigated. For instance, miRNA-770 reduces invasion of breast tumor and suppresses drug insensitivity. miRNA-770 downregulates STMN1 to interfere with metastasis and DOX resistance in breast tumor (Li et al. 2018a). Although this study revealed function of miRNAs in controlling chemo-response and metastasis, more studies should show how their interaction can affect breast tumor. Taking everything together, metastasis is a critical signature in regulating DOX response. Due to role of miRNAs in regulating different biological mechanisms and their abnormal expression in cancer, it was shown that miRNA-mediated regulation of EMT can determine DOX cytotoxicity against breast cancer cells (Fig. 4 and Table 2) (Tong et al. 2020; Yue et al. 2020; Liang et al. 2019; Dou et al. 2020; Chen et al. 2021b; Zheng et al. 2016; Deng et al. 2017).

Fig. 4.

Association of miRNAs controlling cancer metastasis with DOX resistance/sensitivity. miRNAs regulate STMN1, FN1, c-Myc and DUSP4 as well as FBW7 to modulate EMT in cancer cells and affect DOX resistance/sensitivity

Table 2.

The miRNAs involved in regulating metastasis and DOX sensitivity

miRNA	Signaling network	Cancer type	Remarks	References
miRNA-451a	c-Myc/EMT	Lung cancer	Reversing DOX resistance by miRNA-451a overexpression miRNA-451a inhibits EMT via c-Myc signaling suppression to impair tumor metastasis and to increase DOX sensitivity	Tao et al. (2020)
miRNA-137	DUSP4/EMT	Breast cancer	Down-regulation of DUSP4 by miRNA-137 EMT inhibition and subsequent sensitivity to DOX chemotherapy	Du et al. (2019)
miRNA-223	FBXW7/EMT	Colorectal cancer	miRNA-223 stimulates DOX resistance FBXW7 down-regulation by miRNA-223 EMT induction	Ding et al. (2018)
miRNA-200b	FN1/EMT	Breast cancer	FN1 down-regulation by miRNA-200b in breast cancer cells EMT inhibition Metastasis suppression DOX sensitivity	Yang et al. (2017)
miRNA-223	FBW7/EMT	Lung cancer	miRNA-223 down-regulates FBW7 expression to induce EMT and to mediate DOX resistance of tumor cells	Li et al. (2016)
miRNA-770	STMN1/EMT	Breast cancer	miRNA-770 inhibits invasion and drug resistance in breast cancer miRNA-770 reduces STMN1 expression to suppress EMT and to impair metastasis of tumor cells	Li et al. (2018a)
miRNA-424-5p	LINC011116/miRNA-424-5p/EMT	Osteosarcoma	miRNA-424-5p down-regulation by LINC01116 to induce EMT, leading to DOX resistance in cancer cells	Li et al. (2021e)
miRNA-218-5p	Circ-0003998/miRNA-218-5p/EIF5A2	Hepatocellular carcinoma	miRNA-218-5p sponging by circ-0003998 to increase EIF5A2 expression, leading to increased metastasis and EMT induction Triggering DOX resistance	Li et al. (2020)

miRNAs overcoming doxorubicin resistance

General concepts

As a conclusion, metastasis-mediated chemoresistance is influenced by miRNAs and they are classified as protective or lethal factors. AGR2 undergoes overexpression in breast tumor and stimulates DOX resistance. miRNA-135b-5p is suppressed in breast tumor. miRNA-135b-5p downregulates AGR2 to sensitize to DOX (Zhang et al. 2019). HIF-1 causes carcinogenesis during hypoxia and its inhibition by siRNA impairs cancer progression (Liu et al. 2012). It appears that activation of HIF-1 stimulates DOX resistance in breast cancer via promoting activity of P-gp (Doublier et al. 2012). miRNA-194-5p accelerates lung cancer response to DOX. miRNA-194-5p significantly downregulates HIF-1 to impair progression of lung cancer cells (Xia et al. 2021). miRNA-519d-5p demonstrates down-regulation in breast cancer and its upregulation can facilitate DOX sensitivity. The miR-519d-5p-mediated RELA suppression can increase DOX sensitivity (Xi et al. 2021).

miRNAs and drug efflux transporters

ABCC1 and MDR-1 are two members of ATP-binding cassette transporters that are associated with drug resistance and their expression level increases in renal cell carcinoma. These pumps function via using ATP and they transport chemotherapeutic agent out of cancer cells (O'CONNOR 2007; Walsh et al. 2009). The expression level of ABCC1 and MDR-1 are considered as biomarkers for drug resistance in renal cell carcinoma (Walsh et al. 2009). miRNA-210-3p expression significantly decrease in renal cell carcinoma cells, while expression levels of ABCC1 and MDR-1 increase. Low expression of miRNA-210-3p occurs in renal cell carcinoma to promote ABCC1 expression, resulting in MDR-1 overexpression and subsequent DOX resistance (Li et al. 2018b). Depletion of miR-222-3p can diminish P-gp and FOXP2 levels to facilitate response to DOX (Wang et al. 2019b). The upregulation of P-gp depends on FZD5. miR-124 suppresses P-gp-induced DOX resistance through FZD5 downregulation in renal cancer (Long et al. 2015). In addition to FZD5, the PI3K/Akt axis faciliates P-gp activity to mediate DOX insensitivity, while miR-205 suppresses PI3K/Akt through PTEN overexpression to disrupt P-gp-induced DOX resistance (Li et al. 2022). The breast tumor cells also demonstrate P-gp upregulation in DOX resistance development that is reversed by miR-298 overexpression (Bao et al. 2012).

miRNAs, HMGB1 and osteopontin

HMGB1 is a new emerging target in cancer. Exosomal HMGB1 promotes carcinogenesis in lung tumor and prevents DOX cytotoxicity (Wang et al. 2021). In osteosarcoma cells, HMGB1 stimulates protective autophagy to mediate drug resistance (Huang et al. 2012). HMGB1 induces DOX resistance in hepatocellular carcinoma by stimulation of AMPK/mTOR signaling and subsequent induction of autophagy (Li et al. 2021e). Therefore, HMGB1 overexpression evokes DOX resistance and its suppression should be considered in future studies. miRNA-505 is capable of increasing potential of DOX in apoptosis acceleration and upregulation of caspase-3. miRNA-505 interferes with HMGB1/Akt in DOX sensitivity of hepatocellular carcinoma cells and impairing their progression (Lu et al. 2018). The role of osteopontin as a regulator of DOX resistance has been interesting. The response of breast cancer to DOX enhances after silencing osteopontin (Yang et al. 2012). The regulation of osteopontin by miRNA-181c facilitates DOX sensitivity. miR-181c diminishes osteopontin expression to reverse DOX resistance (Han et al. 2019). Therefore, there are a wide variety of miRNAs affecting various downstream targets in cancer that are of importance for determining DOX sensitivity of tumor cells.

miRNAs in doxorubicin resistance induction

General concept

There are miRNAs inducing DOX resistance that are briefly discussed in the current section. One of the mechanisms that DOX uses for reducing tumorigenesis is apoptosis induction via upregulation of caspase-9. Overexpression of miRNA-96-5p promotes progression of hepatocellular carcinoma cells and prevents apoptosis via caspase-9 suppression, causing DOX resistance (Iwai et al. 2018). CKLF1 stimulates IL-6/STAT3 to suppress apoptosis and increase inflammation-mediated tumorigenesis in triggering DOX resistance in hepatocellular carcinoma (Liu et al. 2019d). Osteosarcoma cells exposed to DOX demonstrate increased stemness and metastasis. Apatinib is capable of suppressing STAT3 to decrease SOX2, enhancing DOX sensitivity of osteosarcoma (Tian et al. 2020). The mesenchymal phenotype and DOX resistance in osteosarcoma are suppressed via STAT3 signaling inhibition (Lu et al. 2021b). miRNA-595-5p is involved in preserving stemness of hepatocellular carcinoma cells. Suppressors of STAT3 such as SOCS2, SOCS5, PTPN1 and PTPN11 undergo down-regulation by miRNA-589-5p, causing DOX resistance in hepatocellular carcinoma cells (Long et al. 2018).

Context-dependent function of miRNAs

One of the difficulties in understanding association of miRNAs with DOX resistance is dual miRNA function and their context-dependent function. For instance, miRNA-27b-3p has been shown to increase growth and invasion of colorectal tumor via HOXA10 inhibition (Yang et al. 2019). miRNA-27b-3p downregulates PARP to accelerate metastasis rate of breast cancer (Shen et al. 2020). miRNA-27b-3p suppresses progression of colorectal and breast cancer cells (Chen et al. 2018a; Chen et al. 2017). Therefore, exact function of miRNAs before their targeting in cancer should be revealed. miRNA-27b-3p evokes DOX resistance in thyroid tumor. miRNA-27b-3p downregulates PARPγ to induce DOX insensitivity (Xu et al. 2018). Reducing expression level of tumor-promoting miRNAs can reverse DOX resistance. miRNA-222-3p downregulates FOXP2 to mediate DOX insensitivity in LoVo cells. miRNA-222-3p depletion is associated with DOX sensitivity (Wang et al. 2019b).

The pharmacological intervention in doxorubicin chemosensitivity

As it was mentioned, miRNAs can affect DOX response and they are tightly regulated by upstream mediators. One of the important notes of miRNAs is that they are druggable targets and there are different studies showing that anti-cancer compounds can modulate miRNAs. For instance, curcumin increases expression of miRNA-30a-5p to evoke apoptosis in prostate cancer and to impair proliferation and invasion (Pan et al. 2021). Another study reveals that resveratrol administration impairs progression of liver tumor and preventing EMT via miRNA-186-5p upregulation (Song et al. 2021b). On the other hand, anti-cancer agents have demonstrated synergistic impact with chemotherapeutic agents in sensitizing tumor cells.

Honokiol is a naturally occurring compound that is isolated from Magnolia plants and it demonstrates protective impacts such as anti-inflammatory and anti-oxidant. The in vitro and in vivo experiments have shown capacity of honokiol in suppressing tumor progression. Honokiol suppresses EMT, migration and proliferation of cancer cells and it induces apoptosis via affecting a number of molecular pathways such as STAT3, EGFR and others (Ong et al. 2019; Sengupta et al. 2017; Zang et al. 2020). Honokiol is capable of increasing sensitivity of breast cancer cells to DOX chemotherapy. miRNA-188-5p functions as a tumor-promoting factor in breast cancer and its overexpression is correlated with DOX resistance. Honokiol promotes expression level of miRNA-188-5p to reduce FBXW7 expression, resulting in c-Myc signaling inhibition and subsequent sensitivity to DOX chemotherapy (Yi et al. 2021). Ursolic acid is another compound that is commonly used for purpose of cancer therapy. Ursolic acid interrupts homeostasis of ROS and decreases expression level of survival-related genes to induce apoptosis and reduce progression of intestinal cancer cells (Rawat and Nayak 2021). Ursolic acid induces SP1/cavelolin-1 axis to impair glycolysis and to suppress metastasis of breast tumor cells (Wang et al. 2021d). By inhibiting Akt signaling pathway, ursolic acid impairs progression of esophageal cancer cells and enhances their sensitivity to paclitaxel-mediated apoptosis (Meng et al. 2021). Ursolic acid is beneficial in increasing DOX cytotoxicity against breast tumor cells. For this purpose, ursolic acid reduces expression level of ZEB1-AS1 to increase miRNA-186-5p expression. Then, a significant decrease occurs in expression of ABCC1 to suppress breast tumor progression and to increase DOX sensitivity (Lu et al. 2021c).

Curcumol is an essential oil of Rhizoma Curcumae (Lou et al. 2010) and recent studies have shed some light on its capacity in tumor suppression (Sheng et al. 2021). Curcumol suppresses ability of nasopharyngeal carcinoma cells in migration and invasion via inhibiting PI3K/Akt axis and reducing expression of NCL (Guan et al. 2021). Curcumol has capacity of inducing both apoptosis and autophagy in nasopharyngeal cancer cells to reduce proliferation (Wang et al. 2021e). Notably, curcumol is beneficial in increasing sensitivity of tumor cells to chemotherapy. Curcumol reduces levels of MMP2, P-gp, survivin and β-catenin to increase sensitivity of colon cancer cells to 5flouroruacil chemotherapy (Gao et al. 2021a). A recent experiment has shed some light on the efficacy of curcumol in increasing DOX sensitivity of breast cancer cells. Curcumol promotes expression level of miRNA-181b-2-3p to down-regulate ABCC3, leading to DOX sensitivity of breast tumor cells in vitro and in vivo (Zeng et al. 2020). Thympquinone is another natural product employed in mediating DOX sensitivity of tumor cells (Atteia et al. 2021). Increasing evidence has revealed role of STAT3 signaling in increasing progression of tumor cells and inducing drug resistance. As anti-cancer agent, thymoquinone is able to increase expression level of miRNA-125a-5p to suppress STAT3 signaling, resulting in DOX sensitivity of cancer cells (Atteia et al. 2021). Taking everything together, these studies highlight the fact that anti-tumor agents are able to regulate miRNAs in increasing DOX sensitivity of tumor cells (Hsieh et al. 2020; Gao et al. 2017; Gao et al. 2018). However, studies have focused on using naturally occurring compounds for affecting miRNA expression in cancer cells. Therefore, future studies should use small molecules for targeting miRNAs in increasing DOX sensitivity of cancer cells. Although it has been reported that natural products are emerging compounds for regulation of gene expression in cancer therapy that can affect the drug resistance, immune responses and tumor microenvironment (Garg et al. 2020), a number of challenges should be mentioned. Furthermore, natural products suffer from poor bioavailability and next studies should consider using nano-scale delivery systems for these anti-cancer agents to increase their capacity in miRNA regulation and increasing DOX sensitivity.

Nanobitoechnology in doxorubicin chemotherapy

The previous studies revealed role of miRNAs in regulating DOX resistance/sensitivity of cancer cells. The nano-scale delivery systems have been used for delivery of miRNAs or co-delivery with miRNA and DOX in affecting DOX sensitivity of cancer cells. A recent experiment has used polyplex nanoparticles that are sensitive to ATP and redox for co-delivery of DOX and miRNA-23b in cancer therapy. These polyplexes induced apoptosis, suppressed proliferation of cancer cells and induced cell cycle arrest at S phase. Furthermore, co-delivery of DOX and miRNA-23b by polyplexes reduces MMP-9 expression to suppress migration and invasion of cancer cells. In response to intracellular ATP concentration and redox condition, DOX- and miRNA-23b-loaded polyplexes released DOX and suppressed tumor progression (Tang et al. 2021). In another experiment, DOX- and miRNA-34a-loaded polyplexes were developed for suppressing growth and invasion of tumor cells. This nanocomplex was sensitive to ATP and compared to single cargo, it demonstrated higher anti-cancer activity (reducing cell viability up to 40%). Apoptosis induction and cell cycle arrest were followed upon using nanocomplex for co-delivery of miRNA-34a and DOX (Wang et al. 2017).

Although nanoparticles are of importance for increasing intracellular accumulation of cargo and can provide a platform for co-delivery of DOX and miRNAs, their biocompatibility is of importance and should be considered. Based on the biocompatibility, studies have focused on using micelles that demonstrate high safety profile and can load high amount of drug (Guo et al. 2021; Shi et al. 2021b; Wang et al. 2021f; Zhu, et al. 2021). In a recent experiment, nanomicelles were prepared for co-delivery of DOX and miRNA-519c and for improving their selectivity towards cancer cells, their surface modification with AS1411 aptamer was performed. These micelles were internalized into hepatocellular cancer cells and their modification with AS1411 aptamer increased their cellular uptake and selectivity. Furthermore, delivery of miRNA-519c resulted in down-regulation of ABCG2 that subsequently, significantly promoted accumulation of DOX in hepatocellular carcinoma cells (Liang et al. 2021). In order to improve characteristics of micelles, its combination with polymeric nanoparticles is performed. In this way, an experiment has prepared polymeric hybrid nanomicelles for co-delivery of DOX and miRNA-34a. These nanoparticles mediated lysosomal and endosomal escape of miRNA-34a to prevent its degradation into cells and also, induced nuclear delivery of DOX. The delivered miRNA-34a decreases expression level of Bcl-2, cyclin D1 and CDK6 to suppress growth and metastasis of tumor cells. Then, sensitivity of cancer cells to DOX increases and it can exert its anti-tumor activity (Xie et al. 2019).

Similar to micelles, liposomes also demonstrate high biocompatibility and their long-term safety has resulted in development of nanoformulations for being used in clinic (Chang and Yeh 2012; Peer et al. 2007). In an experiment, stearylamine liposomes were prepared for delivery of anti-miRNA-191 in breast cancer therapy. Delivery of anti-miRNA-191 by liposomes led to growth inhibition, apoptosis induction and decreased invasion of tumor cells. Furthermore, anti-miRNA-191-loaded liposomes increased sensitivity of breast cancer cells to DOX chemotherapy (Sharma et al. 2017). Overall, several benefits result from using nanovehicles for delivery of DOX and miRNAs in cancer therapy. First of all, nanoparticles promote internalization of miRNA and DOX in tumor cells to boost their anti-cancer activity. Encapsulation of miRNAs by nanoparticles may protect them against degradation by enzymes. Furthermore, in order to increase selectivity of nanocarriers towards tumor cells, their modification with ligands has been performed and stimuli-responsive nanocarriers have been developed (Li et al. 2018b; Gajda et al. 2020; Zhao et al. 2017a; Chen et al. 2019; Fan et al. 2017; Fang et al. 2020; Xue et al. 2017). Based on these discussions, it is suggested to use nanoparticles for co-delivery of miRNAs and DOX in cancer chemotherapy. However, most of the studies have ignored effect on molecular pathways that should be evaluated in further experiments (Fig. 5). Table 3 provides a summary of miRNA role in DOX resistance with related molecular pathways.

Fig. 5.

Anti-cancer agents and nanoparticles targeting miRNAs in DOX chemotherapy

Table 3.

The miRNAs and related molecular pathways in DOX chemotherapy

miRNA	Cancer type	Signaling network	Remark	References
miRNA-218-5p	Osteosarcoma	CircSAMD4A/miRNA-218-5p/KLF8	DOX resistance by circSAMD4A Silencing circRNAs induces cell cycle arrest and apoptosis miRNA-218-5p down-regulation by circSAMD4A and overexpression of KLF8	Wei et al. (2020)
miRNA-144-3p	Neuroblastoma	NORAD/miRNA-144-3p/HDAC8	Enhanced progression of tumor cells and association with DOX resistance NORAD decreases miRNA-144-3p expression via sponging and subsequent overexpression of HDAC8	Wang et al. (2020c)
miRNA-140	Colorectal cancer	miRNA-140/PD-L1	Down-regulation of miRNA-140 upon DOX treatment and subsequent upregulation of PD-L1	Naba et al. (2020)
miRNA-4319	Osteosarcoma	LINC00426/miRNA-4319	Overexpression of LINC00426 in colorectal cancer and association with DOX resistance miRNA-4319 down-regulation by LINC00426 to reduce caspase-3 expression	Wang et al. (2020d)
miRNA-137	Osteosarcoma	CircPVT1/miRNA-137/TRIAP1	Stimulation of DOX resistance in cancer cells CircPVT1 silencing decreases proliferation and stimulates apoptosis in tumor cells miRNA-137 down-regulation by circPVT1 to increase TRIAP1 expression	Gao et al. (2021b)
miRNA-222	Breast cancer	miRNA-222/bim	miRNA-222 stimulates DOX resistance in breast cancer Low expression of miRNA-222 stimulates apoptosis miRNA-222 reduces bim expression to induce DOX resistance	Dai, et al. (2019)
miRNA-137-3p	Osteosarcoma	OIP5-AS1/miRNA-137-3p/PTN	OIP5-AS1 induces drug resistance and promotes progression of cancer cells miRNA-137-3p down-regulation by OIP5-AS1 and reduces PTN expression	Sun et al. (2020)
miRNA-370	Osteosarcoma	Circ-0003496/miRNA-370/KLF12	Upregulation of circ-003496 stimulates DOX resistance in tumor cells Circ-0003496 functions as sponge and reduces miRNA-370 expression to increase KLF12 expression	Xie et al. (2020)
miRNA-422a	Gastric cancer	D63785/miRNA-422a/MEF2D	LncRNA D63785 promotes MEF2D expression via miRNA-422a down-regulation, leading to apoptosis inhibition and subsequent DOX resistance in cancer cells	Zhou et al. (2018b)
miRNA-1205	Colorectal cancer	Circ-0006174/miRNA-1205/CCND2	Circ-0006174 stimulates DOX resistance in tumor cells via miRNA-1205 sponging and subsequent overexpression of CCND2	Zhang et al. (2022)
miRNA-137	Neuroblastoma	HDAC8/miRNA-137	Knock-down of HDAC8 promotes miRNA-137 expression and is associated with DOX sensitivity in cancer cells	Zhao et al. (2017b)
miRNA-384	Osteosarcoma	miRNA-384/PTN/β-catenin	Luteolin promotes expression level of miRNA-384 to suppress PTN/β-catenin, leading to an increase in DOX sensitivity of tumor cells	Qin et al. (2022)
miRNA-140-5p	Hepatocellular carcinoma	miRNA-140-5p/PIN1	miRNA-140-5p reduces PIN1 expression to enhance DOX sensitivity of cancer cells	Gao et al. (2021b)
miRNA-378a-3p miRNA-378d	Breast cancer	EZH2/STAT3	Breast cancer cells secrete exosomes containing miRNA-378d and miRNA-378a-3p to induce STAT3 signaling via EZH2 recruitment, leading to DOX resistance	Yang et al. (2021)
miRNA-381-3p	Thyroid carcinoma	miRNA-381-3p/HOXA9	Silencing HOXA9 induces apoptosis and impairs progression of cancer cells miRNA-381-3p decreases HOXA9 expression to induce apoptosis, to suppress growth and metastasis, and to mediate DOX sensitivity	Zhang et al. (2021d)
miRNA-760	Osteosarcoma	CircPRDM2/miRNA-760/EZH2	CircPRDM2 reduces miRNA-760 expression via sponging to induce EZH2 signaling, resulting in DOX resistance	Yuan et al. (2021)
miRNA-221	Breast cancer	-	miRNA-221 prevents apoptosis and stimulates DOX resistance in breast tumor cells	Kheradmand et al. (2021)
miRNA-21-5p	Gastric cancer	miRNA-21-5p/PTEN miRNA-21-5p/TIMP3	Silencing miRNA-21-5p promotes DOX sensitivity of cancer cells miRNA-21-5p decreases PTEN and TIMP3 expression	Chen et al. (2018b)
miRNA-153-5p miRNA-183-5p	Myeloid leukemia	CircPAN3/miRNA/XIAP	CircPAN3 promotes XIAP expression via down-regulation of miRNA-153-5p and miRNA-183-5p to induce DOX resistance in cancer cells	Shang et al. (2019)
miRNA-590-5p	Hepatocellular carcinoma	miRNA-5905p/YAP1	miRNA-590-5p reduces YAP1 expression to impair tumor progression and to increase DOX sensitivity of cancer cells	Chen et al. (2018c)
miRNA-197-5p	Fibrosarcoma	–	miRNA-197-5p may decrease expression and activity of ABCC1 and MVP in preventing drug efflux and suppressing DOX resistance of cancer cells	Jain et al. (2022)
miRNA-381	Breast cancer	miRNA-381/FYN/MAPK	miRNA-381 decreases FYN expression to suppress MAPK signaling, resulting in DOX sensitivity of tumor cells	Mi et al. (2018)
miRNA-376a-3p	Myeloid leukemia	miRNA-376a-3p/MT1X	MT1X down-regulation by miRNA-376a-3p to induce apoptosis and to promote DOX sensitivity of cancer cells	Xin et al. (2022)
miRNA-200c	Breast cancer	miRNA-200c/MDR1	miRNA-200c reduces MDR1 expression to increase DOX sensitivity	Safaei et al. (2022)
miRNA-26a	Osteosarcoma	miRNA-26a/MCL1	miRNA-26a down-regulates MCL1 expression to reverse drug resistance	Liang et al. (2021)
miRNA-495	Ovarian and gastric cancers	miRNA-495/MDR1	miRNA-495 decreases MDR1 expression to increase DOX sensitivity	Zou et al. (2017)
miRNA-34a	Liver cancer	–	miRNA-34a overexpression increases DOX sensitivity	Zheng et al. (2019)

Conclusion

Chemotherapy is a gold standard in treatment of cancer. Although surgical resection is commonly used in cancer therapy, its efficiency significantly decreases during advanced stages and metastasis of tumor cells. Therefore, application of chemotherapy in cancer is inevitable. However, drug resistance is a big barrier towards treatment of cancer patients. DOX is among the anti-cancer agents applied in treatment of cancer and resistance occurs due to mutations in genetic materials. The aim of present study was to investigate role of miRNAs in DOX cytotoxicity against cancer cells. Overall, activation of tumor-promoting pathways such as STAT3 and HIF-1 can occur in mediating DOX resistance in tumor cells. Furthermore, drug efflux transporters such as P-gp demonstrate overexpression in reducing DOX accumulation in cancer cells. Therefore, chance of DOX resistance in cancer is high. miRNAs are major modulators of various molecular pathways and mechanisms in cells. The tumor-promoting miRNAs induce DOX resistance in cancer via apoptosis inhibition, increasing cell cycle progression and providing pro-survival autophagy, while tumor-suppressor miRNAs induce apoptosis, cell cycle arrest and pro-death autophagy in mediating DOX sensitivity. miRNAs can regulate metastasis of cancer cells and affect EMT mechanism to determine response to DOX chemotherapy.

Overall, miRNAs are divided into two categories including tumor-suppressor and tumor-promoting miRNAs in cancer and they were discussed in separate sections. One of the important aspects is regulation of miRNAs by upstream mediators in cancer. LncRNAs and circRNAs are the most well-known regulators of miRNAs in cancer and decrease their expression via sponging to determine DOX cytotoxicity on cancer cells. There are anti-cancer agents such as curcumin, apigenin and curcumol that can affect expression of miRNAs in increasing DOX sensitivity, showing that miRNAs are “druggable targets”. Besides, nanotherapeutics such as micelles and liposomes have been employed for delivery of miRNAs alone or in combination with DOX to suppress tumor-promoting molecular pathways, resulting in DOX sensitivity in cancer cells.

Abbreviations

DOX

Doxorubicin

ROS

Reactive oxygen species

EMT

Epithelial-to-mesenchymal transition

P-gp

P-glycoprotein

miRNAs

MicroRNAs

ncRNAs

Non-coding RNAs

mRNA

Messenger RNA

pri-miRNA

Primary miRNA

pre-miRNA

Precursor miRNA

RISC

RNA-induced silencing complex

EVs

Extracellular vesicles

SCLC

Small-cell lung cancer

NSCLC

Non-small cell lung cancer

AGR2

Anterior gradient 2

HMGB1

High mobility group box 1

lncRNAs

Long non-coding RNAs

circRNAs

Circular RNAs

Declarations

Conflict of interest

The authors declare no conflict of interest.