Cancer Stem Cells as a Potential Target to Overcome Multidrug Resistance

Abstract

Multidrug resistance (MDR), which is a significant impediment to the success of cancer chemotherapy, is attributable to various defensive mechanisms in cancer. Initially, overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) was considered the most important mechanism for drug resistance; hence, many investigators for a long time focused on the development of specific ABC transporter inhibitors. However, to date their efforts have failed to develop a clinically applicable drug, leaving only a number of problems. The concept of cancer stem cells (CSCs) has provided new directions for both cancer and MDR research. MDR is known to be one of the most important features of CSCs and thus plays a crucial role in cancer recurrence and exacerbation. Therefore, in recent years, research targeting CSCs has been increasing rapidly in search of an effective cancer treatment. Here, we review the drugs that have been studied and developed to overcome MDR and CSCs, and discuss the limitations and future perspectives.

Aberrant DNA Methylation of ABC Transporters in Cancer

“…Increasing evidence suggests a crucial role of ABCG2 in intrinsic MDR of cancer stem cells [ 80 , 81 ], a small cell population in cancers, sharing several characteristics of normal stem cells. These characteristics include relative quiescence, the ability to self-renew and resistance to apoptosis [ 82 , 83 ].…”

Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development

“…This can be seen by the continuous poor survival rates of patients with gastrointestinal (GI) cancers, such as colorectal cancer (CRC), pancreatic cancer, gastric cancer, and liver cancer [ 2 ]. One of the major treatment obstacles that has contributed to mortality is resistance to therapy [ 3 , 4 ].…”

“…Resistance to these therapies is generally defined as a poor response of the cancer to a given therapy [ 5 ]. Currently, there are a variety of therapies available for patients with metastatic cancer, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy [ 1 , 3 , 6 , 7 , 8 ]. Depending on the patient’s condition, these therapies can also be used in combination to improve efficacy and patient survival [ 1 ].…”

“…Several mechanisms have been observed to contribute to a cancer’s resistance to therapy, including efflux of chemotherapeutics, resistance to apoptosis, and the repair response to DNA damage [ 5 , 6 , 9 , 10 , 11 ]. As tumor cells are highly heterogeneous, it has been suggested that cancer stem cells (CSCs) exhibit these characteristics and are largely responsible for cancer recurrence and resistance to therapy [ 3 , 6 ].…”

“…In addition, CSC subpopulations, or cancer cells with stem-like qualities, have also been discovered in GI tumor types, including CRC, pancreatic cancer, gastric cancer, and liver cancer [ 2 , 16 , 19 , 20 , 21 , 22 , 23 ]. The stem-like nature of CSCs has been found to contribute to tumor growth, recurrence, and resistance to therapeutics [ 3 , 4 , 6 , 15 , 16 , 24 ]. Furthermore, the plasticity of the CSC state has been observed as a result of the surrounding CSC niche, thus adding an additional obstacle to therapeutic strategies [ 2 , 12 , 14 ].…”