Agents that Inhibit Stem Cell-resistant Chemotherapy

As cancers are heterogeneous, drug discovery efforts are aiming to increase patient survival and will surely need to consider the plasticity of cancer cells (Singh and Settleman, 2010). Cancer stem cells have a higher intrinsic resistance to chemotherapy than do normal cancer cells, and may be the source of post-therapy relapse (Thomas; et al, 2014).

New agents were discovered as anticancer drugs to destroy cancer stem cells that are resistant to chemotherapy. This review paper will focus on some important agents, and these are: Resveratrol, Histone Deacetylase Inhibitors, Disulfiram and metformin.

The first agent is Resveratrol. “Resveratrol is a polyphenol non-flavonoid compound present in strongly pigmented vegetables and fruits” (Pintea and Rugin?, 2014). This compound has antitumor effect. It works by inhibiting tissue necrosis factor beta (TNF- ?) pathway that activates tumor growth. It also suppresses the formation of cancer stem cells of colorectal cancer. The unique feature about this agent is that it sensitizes cancer stem cells to 5-FU. (Buhrmann et al., 2018).

Secondly, mentioning Histone Deacetylase (HDAC) Inhibitors. This class of agents has a significant role in suppressing cancer stem cells of different cancer types by various mechanisms, but not all of them are fully explained. One of these mechanisms is reprogramming gene expression in cancer cells, thus leading to growth arrest and apoptosis. Another mechanism is suppressing self-renewal capability and activating the differentiation of cancer stem cells, resulting in enhanced sensitivity to chemotherapy. There is evidence that these agents can aid the deacetylation of non-histone targets related to cancer stem cells homeostasis; making it target-specific (Lin et al., 2018).

Thirdly, the anti-alcoholism drug Disulfiram was approved for targeting resistant cancer stem cells in both in vivo and in vitro. Disulfiram is aldehyde dehydrogenase (ALDH) inhibitor. It inhibits both ALDH1A1 and ALDH2 isoforms and has shown anti-CSC effects in breast cancer. In addition to ALDH inhibition, it inhibits proteasome and E3 ligases, and considered as DNA-demethylating agent. “This drug has reached phase II clinical trials in the treatment of BGM” (Liu et al., 2013).

Finally, the unexpected agent in inhibiting resistant cancer stem cells (CSC) is metformin. This agent has shown anticancer effect especially against CSC in addition to its antidiabetic effect. Metformin selectively inhibits CSCs via targeting of the AMPK/mTOR/PI3K, insulin/IGF1, Ras/Raf/Erk, Shh, Wnt, TGF?, Notch, and NF-?B signaling pathways, which have many tasks in cell proliferation, self-renewal, differentiation, metastasis and metabolism. It’s important to notice that even metformin –as monotherapy or in combination with chemotherapy- has anti-CSC activity; further clinical trials are needed for additional emphasis of this effect (Saini and Yang, 2017).

To conclude, cancer stem cells are more resistant to conventional chemotherapeutics than the majority of cancer cells, and survival of cancer stem cells likely contributes to tumor recurrence. Theoretically, eliminating cancer stem cells through targeted therapies would increase the efficacy of our existing treatments and lead to more favorable long-term prognoses for many cancer types. Drug discovery nowadays is directed towards cancer field and aims to treat cancer and prevent cancer relapse via targeting cancer stem cells. Some agents were existed before like Disulfiram and metformin, and other agents are totally new.

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