The enhanced efflux of chemotherapeutic agents resulting in lower intracellular drug concentration is one of the major causes of chemotherapeutic resistance [9]. Trans-membrane transporters that are responsible for drug efflux are mainly from the ABC transporter subfamily. There are 48 ABC genes classified into 7 subfamilies [10]. ATP-binding cassette (ABC) proteins such as P-glycoprotein (P-gp) are present on the surface of the cell membrane and are responsible for the absorption and excretion of a variety of chemical compounds. P-gp is highly overexpressed on the endothelial cell surface and leads to reduced drug penetration at the specific tumor site. P-gp can efflux a variety of anticancer agents, including anthracyclines, taxanes, and vinca alkaloids, to decrease the intracellular drug concentration [11]. A correlation between the overexpression of P-gp and increased resistance is particularly associated with paclitaxel, doxorubicin, vinblastine, etoposide, and olaparib [12,13]. In some types of hematological cancer, an initial low expression and then a dramatic increase in the level of P-gp (ABCB1) after chemotherapy has been observed [14]. ABCG2 is mainly involved in drug efflux in breast tumor resistance. It can transport both cationic and anionic drugs including chemotherapeutic agents and imatinib [15]. The efflux of drugs can also be mediated by extracellular vesicles (EVs), MRP1, and BCRP proteins. The functionality of efflux pump also depends on the composition and characteristics of the plasma membrane [16].

Certain genetic factors also contribute to chemotherapeutic resistance such as gene mutation, amplification, and epigenetic alterations.

Gene mutations mostly occur in tumor cells and are one of the major causes of chemotherapeutic resistance and poor treatment response. The basis for the development of MDR in cancer cells is their aneuploidy nature [17]. During the process of mitosis, the reassortment of chromosomes can lead to the loss of drug-sensitive genes with the resultant loss of chemotherapeutic resistance. By contrast, normal cells that do not lose or gain a chromosome retain their drug sensitivity [18]. Mutation in TP53 in cancer cells is a well-known biomarker for tumorigenesis. TP53 is responsible for regulating the cell cycle and inducing apoptosis in cases of genotoxic stress during the process of replication. Mutation in TP53 genes also leads to the loss of tumor-suppressive activities [18]. Similarly, mutations in BCR-ABL genes associated with drug-binding regions lead to resistance in chronic myeloid leukemia (CML) [19]. Some studies support a correlation between the reactivation of BCR-ABL genes and remission of CML [20].

Some chemotherapeutic agents such as methotrexate act by inhibiting key enzymes such as dihydrofolate reductase that control cell proliferation. A few types of cancer such as leukemia overcome this inhibition by enhancing the transcription of genes that encode the enzyme. This process is related to the synthesis of a specific region of a chromosome, and these amplified sequences are identified with double chromosomes. This results in the increased production of enzymes, and drug treatment strategies are not able to inhibit these enzymes, leading to reduced therapeutic activity [21]. The amplification of human epidermal growth factor receptor-2 (HER-2) leads to modification in a variety of genes and increases chemotherapeutic resistance to anti-HER-2 drugs [22].

Epigenetic alterations also contribute to chemotherapeutic resistance. Epigenetic alterations include histone modification, DNA methylation, non-coding RNA-related alterations, and chromatin remodeling [23]. DNA hypermethylation or hypomethylation is a potential factor contributing to cancer drug resistance. During tumorigenesis, the epigenome undergoes some alterations including the loss of DNA methylation, histone modification, and changes in miRNA expression [24,25]. The demethylation of the ABCB1 gene results in the decreased accumulation of chemotherapeutic agents in cancer cells. Epigenetic alterations may also affect DNA repair systems. Epigenetic changes related to miRNAs play a key role in the development of chemotherapeutic resistance in cancer cells. Studies have shown that miRNA affects the sensitivity of cancer cells to anticancer drugs through epigenetic changes [26].

The results of various studies indicate an association between inflammation and cancer. Chronic inflammatory responses lead to tumor invasion. There is increased production of interleukin (IL-4, IL-6, and IL-8) and growth factors in MDR tumors compared with drug-sensitive cancers [27,28]. IL-6 can affect different biological processes such as cell growth and death by increasing the expression of the ABCB1 gene. There is convincing evidence of a correlation between the presence of IL-6 in tumor stroma and the MDR of gastric tumors [29]. The enhanced activity of protein kinase-C and extracellular matrix (ECM) in breast cancer is associated with increased resistance to chemotherapy [30,31].

Tumor cells also develop resistance to various chemotherapeutic drugs by increasing their ability to repair DNA damage. DNA repair endonuclease XPF and DNA excision repair protein ERCC-1 are essential for the repair of DNA damage induced by platinum-based agents [32]. There is a correlation between the increased expression of XPF and ERCC-1 and tumor resistance to cisplatin. Cisplatin and 5-fluorouracil both kill tumor cells by inducing DNA damage. Some genes involved in DNA repair mechanisms such as FEN1 and FANCG are reported to be overexpressed in 5-FU-resistant colon cancers [4].

Some enzymes responsible for drug metabolism can contribute to chemotherapeutic resistance. Drug-metabolizing enzymes are an essential part of phase-I and phase-II metabolism. Cytochromes P450 are key enzymes responsible for the metabolism of a variety of drugs. An increased expression of CYP1B1 has been observed in some cancer cells that modify the biotransformation of paclitaxel, docetaxel, and flutamide [33]. An increased expression of the CYP2A6 enzyme, which is involved in the metabolism of cyclophosphamide and 5-fluorouracil, has been observed in breast cancer tissues. The overexpression of CYP1B1 and CYP2A7 in different cancers is related to increased resistance to different chemotherapeutic agents [34].