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Review
. 2018 Dec 4;10(12):483.
doi: 10.3390/cancers10120483.

Sensitization of Drug Resistant Cancer Cells: A Matter of Combination Therapy

Meghan Leary  1 , Sarah Heerboth  2 , Karolina Lapinska  3 , Sibaji Sarkar  4   5   6
Affiliations
Review

Sensitization of Drug Resistant Cancer Cells: A Matter of Combination Therapy

Meghan Leary et al. Cancers (Basel). .

Abstract

Cancer drug resistance is an enormous problem. It is responsible for most relapses in cancer patients following apparent remission after successful therapy. Understanding cancer relapse requires an understanding of the processes underlying cancer drug resistance. This article discusses the causes of cancer drug resistance, the current combination therapies, and the problems with the combination therapies. The rational design of combination therapy is warranted to improve the efficacy. These processes must be addressed by finding ways to sensitize the drug-resistant cancers cells to chemotherapy, and to prevent formation of drug resistant cancer cells. It is also necessary to prevent the formation of cancer progenitor cells by epigenetic mechanisms, as cancer progenitor cells are insensitive to standard therapies. In this article, we emphasize the role for the rational development of combination therapy, including epigenetic drugs, in achieving these goals.

Keywords: cancer drug sensitization; cancer progenitor cell; cancer therapy; chemotherapy; combination therapy; drug resistance; epigenetics; histone modification; methylation; stem cell.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
This figure demonstrates a model of possible causes of cancer drug resistance. All of these pathways could be regulated by extracellular signaling, epigenetic events, and intracellular events and signaling. A combination of all these elements produces cancer progenitor cells and sustains their production, even when cancer is apparently in remission.
Figure 2
Figure 2
(A) Figure 2A depicts a model of antagonistic combination therapy. Drug A, a metabolic product of Drug A, or one of the downstream effectors blocks the effect of Drug B, or the downstream pathway of Drug B, inhibits the effect of combination therapy. (B) Figure 2B depicts a model of synergistic combination therapy. Drug A, a metabolic product of Drug A, or one of the downstream effectors, enhances the effect of Drug B or the downstream pathway of Drug B, and vice versa, enhancing the effect of combination therapy. (C) Figure 2C depicts a model of the positive effects of a combination therapy including epigenetic drugs. This combination kills the cancer progenitor cell, sensitizes cancer drug-resistant cells, inhibits the production of drug-resistant cancer cells, and inhibits the production of cancer progenitor cells.
Figure 2
Figure 2
(A) Figure 2A depicts a model of antagonistic combination therapy. Drug A, a metabolic product of Drug A, or one of the downstream effectors blocks the effect of Drug B, or the downstream pathway of Drug B, inhibits the effect of combination therapy. (B) Figure 2B depicts a model of synergistic combination therapy. Drug A, a metabolic product of Drug A, or one of the downstream effectors, enhances the effect of Drug B or the downstream pathway of Drug B, and vice versa, enhancing the effect of combination therapy. (C) Figure 2C depicts a model of the positive effects of a combination therapy including epigenetic drugs. This combination kills the cancer progenitor cell, sensitizes cancer drug-resistant cells, inhibits the production of drug-resistant cancer cells, and inhibits the production of cancer progenitor cells.
Figure 3
Figure 3
Figure 3 shows a model of how combination therapy, including epigenetic drugs, possibly affects the metastatic state of a tumor. The top panel shows that if the tumor is detected early, and if patients are given low doses of epigenetic drugs after apparent remission, it will reduce the chance of relapse. The lower panel shows that even if the tumor has metastasized, the likelihood of survival is increased if epigenetic drugs are introduced in combination.
See this image and copyright information in PMC

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