SM Journal of Pharmacology and Therapeutics


Novel Function of Old Drugs in Targeting Cancer Stem Cells

Haineng Xu*


Cancer is a severe disease and growing as the leading cause of disease induced death. It leads to 8.2 million death in 2012 and got 14.2 million cases. This is an enormous burden to the patients, their families and the whole society. Currently the major ways for cancer therapy are mostly three traditional methods: surgery, chemotherapy and radiotherapy [1]. In the recent years, with the developing of biochemical researches, some bio-therapeutic methods were applied on cancer therapy. Immunotherapy [2], receptor kinase targeting therapy [3] and gene therapy [4] were developed. These novel approaches and their combination with the traditional methods dramatically improved the efficiency in some types of cancers. However, some cancer cells may relapse after treatment and some cancer cells may resist to chemo- or radio-therapies. Also, some cancers have already metastasized at the time of diagnosis. Due to these issues, it is still a big challenge in developing more efficient drugs to eliminate cancers.

In 1994, Lapidot, T, et al. found that the CD34+CD38- cells in leukemia could engraft SCID mice to generate amount of colony-forming progenitors. However, the other cells populations didn’t possess this property [1]. Al-Hajj, M, et al. reported in 2003 that the CD24- cells could produce tumors much stronger than the CD24+ cells [5]. There were amount of subsequently reports on the similar phenomenon in various cancers. A specific small subpopulation plays greater roles than other cells in cancer. They called these as cancer-initiating cells or Cancer Stem Cells (CSCs). As the developing of this field, researchers find that the CSCs are critical for cancer progression, chemo- or radio- resistance, cancer relapse and metastasis. They are responsible for the renew and are considered as the root of the cancer. For the traditional methods, the bulk cancer cells are killed but not the CSCs as its quiescent status. The tumors shrink in a short time during the treatment. However, after the treatment, some CSCs will release from its quiescent status, proliferate and differentiate into bulk cancer cells. Also, some CSCs will keep their renewal property. These make the cancer relapse in a long time after treatment. If we utilize CSCs targeting drugs to treat cancers, the renewal property of cancers will be prohibited. The tumors will shrink in a long time [6].

Due to the critical role of CSCs in cancer therapy, multiple approaches are introduced to target cancer stem cells. As the cancer stem cells are able to pump the chemo-drugs out of cells through their surface ATP binding cassette transporter, cancer stem cells are resistant to chemo-therapy. Oncolytic viruses could replicate in CSCs, unable to be pumped out and directly lyzed the CSCs [7,8]. Researchers also designed shRNAs or inhibitors to target the self-renewal associated pathway, like Wnt [9], Notch [10] and Hedgehog [11], to block the self-renew of CSCs. Besides these specific designed approaches, people use unbiased drug screen to search efficient drug in targeting CSCs as well [12,13].

For searching efficient drugs in targeting CSCs, researchers used unidentified drug pool or FDA approved drugs to treat CSCs. The effect of the small molecules on the cell viability or stemness on CSCs will be evaluated. One or several putative efficient drugs will be selected for further confirmation. In 2012, Sachlos, E, et al. used compound libraries to screen drugs on the neoplastic and normal human Pluripotent Stem Cells (hPSC). The cell viability and differentiation were both considered for drug selection. The authors found an interesting drug, thoridazine, an antipsychotic drug. It was also demonstrated with inhbitory effect on leukemia and breast CSCs in this paper. Thoridazine is an inhibitor of dopamine receptor D2 family proteins [13]. It has already been approved by FDA and classically used to treat patients with psychotic problems.

The novel function of the old drug attracted lots of attentions. People found inhibitory ability of thioridazine on cancer cells or CSCs in various types of cancers, gastric cancer, cervical cancer, liver cancer, glioblastoma, endometrial cancer and ovarian cancer. Thioridazine could induce CSCs apoptosis and inhibit cell viability in vitro. It also prevented tumor growth in vivo. Thioridazine regulates the key pathways, FAK-mTOR [14], PI3K/Akt/mTOR, to alter cells viability in vitro and in vivo [15]. Thioridazine was also wrapped into nanomaterial to target CSCs [16]. Besides the effect of thoridazine, the expression of dopamine receptors and their correlation with cancer prognosis were analyzed. These further support the function of thoridazine in targeting CSCs.

In the Cell paper, Sachlos, E. et al. found the novel anti-CSCs function of an old antipsychotic drug thioridazine. Its effect was further confirmed by other researchers in the various kinds of cancers. As thioridazine is a FDA approved drug, it will easily be used for clinical research on cancer by targeting CSCs. This is a big advantage in comparison with new developed drugs. Its application in cancer therapy will be largely shortened.

Besides thioridazine, some other small molecules were also discovered through screening. In 2009, by high-throughput screen, Gupta PB disclosed that salinomycin reduced the CSCs population over 100 fold than paclitaxel, a commonly used chemotherapeutic drug for breast cancer [12]. Salinomycin could inhibit CSCs selfrenew by inhibiting Wnt signaling and selectively induced cancer cells apoptosis [9]. Its anti-CSCs effect was demonstrated in some other cancers as well, like gastric CSCs and lung CSCs. In 2014, Jiang, et al. discovered the anti-tumor function of pitavastatin, a drug regulating blood cholesterol, in glioblastoma through drug screen in NIH clinical collection compounds. Subsequently research found that pitavastatin could inhibitor glioblastoma stem cells [17,18]. Antiprotozoal drug emetine [19], anthelmintic drug Niclosamide [20] and some other drugs were discovered with novel function in targeting cancer or CSCs.

As the critical role of CSCs in various cancers, developing efficient approaches to target CSCs is important in cancer therapy. Developing specific oncolytic viruses to lyze the CSCs, inhibiting CSCs self-renew by targeting key pathways or discovering effective drug through unbiased drug screen are three major ways of getting drugs to target CSCs. Discovering novel function of FDA approved old drug will shorten its application on clinic as its safety has already been demonstrated. More researches need to do this to search novel effective drugs or further demonstrate the current putative efficient drugs.


  1. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994; 367: 645-648.
  2. Haji-Fatahaliha M, Hosseini M, Akbarian A, Sadreddini S, Jadidi-Niaragh F, Yousefi M. CAR-modified T-cell therapy for cancer: an updated review. Artif Cells Nanomed Biotechnol. 2015.
  3. Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol. 2008; 21: S16-22.
  4. Xu HN, Huang WD, Cai Y, Ding M, Gu JF, Wei N, Sun LY. HCCS1-armed, quadruple-regulated oncolytic adenovirus specific for liver cancer as a cancer targeting gene-viro-therapy strategy. Mol Cancer. 2011; 10: 133.
  5. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ and Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003; 100: 3983-3988.
  6. Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts. Annu Rev Med. 2007; 58: 267-284.
  7. Cripe TP, Wang PY, Marcato P, Mahller YY, Lee PW. Targeting cancer-initiating cells with oncolytic viruses. Mol Ther. 2009; 17: 1677-1682.
  8. Yang Y, Xu H, Huang W, Ding M, Xiao J, Yang D, Li H. Targeting lung cancer stem-like cells with TRAIL gene armed oncolytic adenovirus. J Cell Mol Med. 2015; 19: 915-923.
  9. Lu D, Choi MY, Yu J, Castro JE, Kipps TJ, Carson DA. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci U S A. 2011; 108: 13253-13257.
  10. Shih IeM, Wang TL. Notch signaling, gamma-secretase inhibitors and cancer therapy. Cancer Res. 2007; 67: 1879-1882.
  11. Tang SN, Fu J, Nall D, Rodova M, Shankar S, Srivastava RK. Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. International journal of cancer. Journal international du cancer. 2012; 131: 30-40.
  12. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009; 138: 645-659.
  13. Sachlos E, Risueño RM, Laronde S, Shapovalova Z, Lee JH, Russell J, Malig M. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell. 2012; 149: 1284-1297.
  14. Byun HJ, Lee JH, Kim BR, Kang S, Dong SM, Park MS, Lee SH. Anti-angiogenic effects of thioridazine involving the FAK-mTOR pathway. Microvasc Res. 2012; 84: 227-234.
  15. Kang S, Dong SM, Kim BR, Park MS, Trink B, Byun HJ, Rho SB. Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells. Apoptosis. 2012; 17: 989-997.
  16. Ke XY, Lin Ng VW, Gao SJ, Tong YW, Hedrick JL, Yang YY. Co-delivery of thioridazine and doxorubicin using polymeric micelles for targeting both cancer cells and cancer stem cells. Biomaterials. 2014; 35: 1096-1108.
  17. Jiang P, Mukthavaram R, Chao Y, Bharati IS, Fogal V, Pastorino S, et al. Novel anti-glioblastoma agents and therapeutic combinations identified from a collection of FDA approved drugs. Journal of translational medicine. 2014; 12: 13.
  18. Jiang P, Mukthavaram R, Chao Y, Nomura N, Bharati IS1, Fogal V, Pastorino S. In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells. Br J Cancer. 2014; 111: 1562-1571.
  19. Visnyei K, Onodera H, Damoiseaux R, Saigusa K, Petrosyan S, De Vries D, Ferrari D. A molecular screening approach to identify and characterize inhibitors of glioblastoma stem cells. Mol Cancer Ther. 2011; 10: 1818-1828.
  20. Wang YC, Chao TK, Chang CC, Yo YT, Yu MH, Lai HC. Drug screening identifies niclosamide as an inhibitor of breast cancer stem-like cells. PLoS One. 2013; 8: e74538.

Citation: Haineng Xu. Novel Function of Old Drugs in Targeting Cancer Stem Cells. SM J Pharmac Ther. 2016; 2(1): 1010.

Download PDF