Multiple genetic and epigenetic interacting mechanisms contribute to clonally selection of drug‐resistant tumors: Current views and new therapeutic prospective

Abstract

Successful treatment of cancer requires a clear understanding of drug-resistance mechanism. Cancer patient are often treated with standard protocols without considering individual difference in chemosensitivity, whereas the efficacy of anticancer drug varies widely among individual patients. Since chemosensitivity involves multiple interacting factors, it is not sufficient to investigate a single gene or factor to fix chemoresistance. Along with affecting disease progression, the synergism between genetic and epigenetic abnormalities can contribute to convert a sensible tumor cell in a resistant one. Unlike genetic changes, epigenetic changes are potentially reversible. Therefore, treatment with DNA methylation inhibitors can reactivate the expression of genes improperly methylated and can reverse many aspect of cancer phenotype such as drug resistance. The demethylating agents are used in the treatment of several kind of tumor, but toxicity and the potential outcome on the normal methylation patterns have always been concern of researchers and clinicals. It is necessary to create individual chemosensitivity-chemoresistance maps in order to identify the combination of drugs for optimized treatments. An overview on genetic and epigenetic events contributing to clonally selection of chemotherapeutic-resistant tumors is discussed.

Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin

“…We identified 137 miRNA genes (63 up-regulated and 75 down-regulated) that were differentially expressed (P < 0.05) in the MCF-7/DOX cells compared with the parental MCF-7 cells (Supplementary Table S1). 4 Furthermore, 84 of these miRNA genes were differentially expressed at a level of P < 0.01 (Fig. 1A).…”

“…The absence of convincing evidence that genetic changes have a role in acquired clinical resistance following anticancer therapy undermines the genetic hypothesis (5). In contrast, conclusive data show that increased resistance of cancer cells to chemotherapeutic agents is associated with epigenetic alterations that include changes in DNA methylation and histone modifications (4,5,7). The karyotypic hypothesis (8) is closely related to the epigenetic one in view of the wellknown fact that epigenetic changes are a necessary prerequisite to karyotypic changes (9).…”

Long Non-coding RNAs and Drug Resistance

“…With the development of new technologies in combination of bioinformatics, more and more genes related to drug resistance are discovered or predicted (Potti et al, 2006;Raguz et al, 2008;Crijns et al, 2009;Etemadmoghadam et al, 2009). Drug resistance results from diverse factors, including individual variations in patients, genetic and epigenetic changes within tumors (Roberti et al, 2006;Tan et al, 2010) such as mutations, translocations, deletions and amplifications of coding genes or promoter regions, gene rearrangement (Fojo T, 2007), alteration of tumor microenvironment and tumor stromal cell components (Bouzin et al, 2007), self-protection of cancer stem cells (Rosen et al, 2009), epithelial-mesenchymal transition (Han et al, 2014), energy metabolism and hypoxia (Broxterman et al, 1991;Robey et al, 2009;Ruan et al, 2009). In addition, other reasons like classical drug efflux (Gottesman et al, 2006), acceleration of drug metabolism and decreasing sensitivity to induction of apoptosis (Janne et al, 2009;Coley, 2010) also result in drug resistance.…”

The epimer of kaurenoic acid from Croton antisyphiliticus is cytotoxic toward B-16 and HeLa tumor cells through apoptosis induction

“…This has become a challenge that has prompted the search for new types of compounds with suitable pharmacological properties to overcome the different resistance mechanisms involving decreased uptake of water-soluble drugs, changes in cell metabolism that affect the capacity of cytotoxic drugs, and increased energy-dependent efflux of hydrophobic drugs that easily enter the cells by diffusion through the plasma membrane (Roberti et al, 2006;Szakacs et al, 2006). Natural products are a rich source of new drugs, and numerous substances with cytotoxic activity have been isolated from natural products of plant origin (Gordaliza, 2007;Newman and Cragg, 2012).…”