HER2 Support Group Forums - View Single Post - Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Cell

Rich66 · 11-14-2009, 04:45 PM

Expert Opin Drug Metab Toxicol. 2009 Dec;5(12):1529-42.
ABCG2: the key to chemoresistance in cancer stem cells?

An Y, Ongkeko WM.
Stanford University School of Medicine, Stanford, CA 94305, USA.

LINK

Abstract

Multi-drug chemoresistance remains one of the most common reasons for chemotherapy failure. The membrane transporter protein ABCG2/BCRP1 has been shown in vitro to effectively reduce the intracellular concentrations of several prominent anticancer chemotherapeutic agents such as mitoxantrone and doxorubicin. Intriguingly, cancer stem cells are known to be characterized by multi-drug chemoresistance. Taking into account that the ABCG2(+) subset of tumor cells are often enriched with cells with cancer stem-like phenotypes, it has been proposed that ABCG2 activity underlies the ability of cancer cells to regenerate post-chemotherapy. Furthermore, we also review evidence suggesting that tyrosine kinase inhibitors, including imatinib and gefitinib, are both direct and downstream inactivators of ABCG2 and, therefore, serve as candidates to reverse cancer stem cell chemoresistance and potentially target cancer stem cells.

PMID: 19708828 [PubMed - indexed for MEDLINE]

Int J Cancer. 2010 Jul 8. [Epub ahead of print]
Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population.

Luk SU, Yap WN, Chiu YT, Lee DT, Ma S, Lee TK, Vasireddy RS, Wong YC, Ching YP, Nelson C, Yap YL, Ling MT.
Department of Anatomy, the University of Hong Kong, Hong Kong, SAR, China.
Abstract

Emerging evidence supports that prostate cancer originates from a rare sub-population of cells, namely prostate cancer stem cells (CSCs). Conventional therapies for prostate cancer are believed to mainly target the majority of differentiated tumor cells but spare CSCs, which may account for the subsequent disease relapse after treatment. Therefore, successful elimination of CSCs may be an effective strategy to achieve complete remission from this disease. Gamma-tocotrienols (gamma-T3) is one of the vitamin-E constituents which have been shown to have anticancer effects against a wide-range of human cancers. Recently, we have reported that gamma-T3 treatment not only inhibits prostate cancer cell invasion but also sensitizes the cells to docetaxel-induced apoptosis, suggesting that gamma-T3 may be an effective therapeutic agent against advanced stage prostate cancer. Here, we demonstrate for the first time that gamma-T3 can down-regulate the expression of prostate CSC markers (CD133/CD44) in androgen independent (AI) prostate cancer cell lines (PC-3 & DU145), as evident from western blotting analysis. Meanwhile, the spheroid formation ability of the prostate cancer cells was significantly hampered by gamma-T3 treatment. In addition, pre-treatment of PC-3 cells with gamma-T3 was found to suppress tumor initiation ability of the cells. More importantly, while CD133-enriched PC-3 cells were highly resistant to docetaxel treatment, these cells were as sensitive to gamma-T3 treatment as the CD133-depleted population. Our data suggest that gamma-T3 may be an effective agent in targeting prostate CSCs, which may account for its anticancer and chemosensitizing effects reported in previous studies.

PMID: 20617516 [PubMed - as supplied by publisher]

Cancer Lett. 2006 Jun 18;237(2):180-7. Epub 2005 Jul 12.
Fluoxetine and reversal of multidrug resistance.

Peer D, Margalit R.
Department of Biochemistry, George S. Wise Life Science Faculty, Tel Aviv University, Tel Aviv 69978, Israel
This review centers on recent findings with respect to modulating cancer multidrug resistance (MDR) with the well-known antidepressant fluoxetine (prozac). The MDR phenomena and mechanisms are discussed, including the roles of ABC transporters as MDR-pumps and the potential involvement of cancer stem cells. The three generations of MDR reversal agents (chemosensitizers) are reviewed, introducing the concept of single-pump and multi-pump agents. The current status of chemosensitization is summarized, pointing-out the need for additional agents and outlining experimental criteria for testing novel candidates. Major in vitro and in vivo findings are summarized showing that fluoxetine is a chemosensitizer of the multi-pump type, and proposing it be considered a fourth-generation chemosensitizer. In concluding, we contemplate future prospects of modulating MDR in the clinic.

PMID: 16014320 [PubMed - indexed for MEDLINE]

Cancer Res. 2004 Oct 15;64(20):7562-9.
Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models.

Peer D, Dekel Y, Melikhov D, Margalit R.
Department of Biochemistry, the George S. Wise Life Science Faculty, Tel Aviv University, Tel Aviv, Israel.
Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins, is a major reason for poor responses and failures in cancer chemotherapy. MDR modulators (chemosensitizers) were found among drugs approved for noncancer indications and their derivatives. Yet toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Among newly designed chemosensitizers, some still suffer from toxicity and adverse effects, whereas others progressed to clinical trials. Diversities among tumors and among MDR pumps indicate a need for several clinically approved MDR modulators. Here we report for the first time that fluoxetine (Prozac), the well-known antidepressant, is a highly effective chemosensitizer. In vitro, fluoxetine enhanced (10- to 100-fold) cytotoxicity of anticancer drugs (doxorubicin, mitomycin C, vinblastine, and paclitaxel) in drug-resistant but not in drug-sensitive cells (5 and 3 lines, respectively). Fluoxetine increased drug accumulation within MDR-cells and inhibited drug efflux from those cells. In vivo, fluoxetine enhanced doxorubicin accumulation within tumors (12-fold) with unaltered pharmacokinetics. In four resistant mouse tumor models of both syngeneic and human xenograft, combination treatment of fluoxetine and doxorubicin generated substantial (P < 0.001) improvements in tumor responses and in survivals (2- to 3-fold). Moreover, fluoxetine reversed MDR at doses that are well below its human safety limits, free of the severe dose-related toxicity, adverse effects, and poor solubility that are obstacles to other chemosensitizers. This low-dose range, together with the findings reported here, indicate that fluoxetine has a high potential to join the arsenal of MDR reversal agents that may reach the clinic.

PMID: 15492283 [PubMed - indexed for MEDLINE]

11-14-2009, 04:45 PM	#48
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce Expert Opin Drug Metab Toxicol. 2009 Dec;5(12):1529-42. ABCG2: the key to chemoresistance in cancer stem cells? An Y, Ongkeko WM. Stanford University School of Medicine, Stanford, CA 94305, USA. LINK Abstract Multi-drug chemoresistance remains one of the most common reasons for chemotherapy failure. The membrane transporter protein ABCG2/BCRP1 has been shown in vitro to effectively reduce the intracellular concentrations of several prominent anticancer chemotherapeutic agents such as mitoxantrone and doxorubicin. Intriguingly, cancer stem cells are known to be characterized by multi-drug chemoresistance. Taking into account that the ABCG2(+) subset of tumor cells are often enriched with cells with cancer stem-like phenotypes, it has been proposed that ABCG2 activity underlies the ability of cancer cells to regenerate post-chemotherapy. Furthermore, we also review evidence suggesting that tyrosine kinase inhibitors, including imatinib and gefitinib, are both direct and downstream inactivators of ABCG2 and, therefore, serve as candidates to reverse cancer stem cell chemoresistance and potentially target cancer stem cells. PMID: 19708828 [PubMed - indexed for MEDLINE] Int J Cancer. 2010 Jul 8. [Epub ahead of print] Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population. Luk SU, Yap WN, Chiu YT, Lee DT, Ma S, Lee TK, Vasireddy RS, Wong YC, Ching YP, Nelson C, Yap YL, Ling MT. Department of Anatomy, the University of Hong Kong, Hong Kong, SAR, China. Abstract Emerging evidence supports that prostate cancer originates from a rare sub-population of cells, namely prostate cancer stem cells (CSCs). Conventional therapies for prostate cancer are believed to mainly target the majority of differentiated tumor cells but spare CSCs, which may account for the subsequent disease relapse after treatment. Therefore, successful elimination of CSCs may be an effective strategy to achieve complete remission from this disease. Gamma-tocotrienols (gamma-T3) is one of the vitamin-E constituents which have been shown to have anticancer effects against a wide-range of human cancers. Recently, we have reported that gamma-T3 treatment not only inhibits prostate cancer cell invasion but also sensitizes the cells to docetaxel-induced apoptosis, suggesting that gamma-T3 may be an effective therapeutic agent against advanced stage prostate cancer. Here, we demonstrate for the first time that gamma-T3 can down-regulate the expression of prostate CSC markers (CD133/CD44) in androgen independent (AI) prostate cancer cell lines (PC-3 & DU145), as evident from western blotting analysis. Meanwhile, the spheroid formation ability of the prostate cancer cells was significantly hampered by gamma-T3 treatment. In addition, pre-treatment of PC-3 cells with gamma-T3 was found to suppress tumor initiation ability of the cells. More importantly, while CD133-enriched PC-3 cells were highly resistant to docetaxel treatment, these cells were as sensitive to gamma-T3 treatment as the CD133-depleted population. Our data suggest that gamma-T3 may be an effective agent in targeting prostate CSCs, which may account for its anticancer and chemosensitizing effects reported in previous studies. PMID: 20617516 [PubMed - as supplied by publisher] Cancer Lett. 2006 Jun 18;237(2):180-7. Epub 2005 Jul 12. Fluoxetine and reversal of multidrug resistance. Peer D, Margalit R. Department of Biochemistry, George S. Wise Life Science Faculty, Tel Aviv University, Tel Aviv 69978, Israel This review centers on recent findings with respect to modulating cancer multidrug resistance (MDR) with the well-known antidepressant fluoxetine (prozac). The MDR phenomena and mechanisms are discussed, including the roles of ABC transporters as MDR-pumps and the potential involvement of cancer stem cells. The three generations of MDR reversal agents (chemosensitizers) are reviewed, introducing the concept of single-pump and multi-pump agents. The current status of chemosensitization is summarized, pointing-out the need for additional agents and outlining experimental criteria for testing novel candidates. Major in vitro and in vivo findings are summarized showing that fluoxetine is a chemosensitizer of the multi-pump type, and proposing it be considered a fourth-generation chemosensitizer. In concluding, we contemplate future prospects of modulating MDR in the clinic. PMID: 16014320 [PubMed - indexed for MEDLINE] Cancer Res. 2004 Oct 15;64(20):7562-9. Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models. Peer D, Dekel Y, Melikhov D, Margalit R. Department of Biochemistry, the George S. Wise Life Science Faculty, Tel Aviv University, Tel Aviv, Israel. Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins, is a major reason for poor responses and failures in cancer chemotherapy. MDR modulators (chemosensitizers) were found among drugs approved for noncancer indications and their derivatives. Yet toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Among newly designed chemosensitizers, some still suffer from toxicity and adverse effects, whereas others progressed to clinical trials. Diversities among tumors and among MDR pumps indicate a need for several clinically approved MDR modulators. Here we report for the first time that fluoxetine (Prozac), the well-known antidepressant, is a highly effective chemosensitizer. In vitro, fluoxetine enhanced (10- to 100-fold) cytotoxicity of anticancer drugs (doxorubicin, mitomycin C, vinblastine, and paclitaxel) in drug-resistant but not in drug-sensitive cells (5 and 3 lines, respectively). Fluoxetine increased drug accumulation within MDR-cells and inhibited drug efflux from those cells. In vivo, fluoxetine enhanced doxorubicin accumulation within tumors (12-fold) with unaltered pharmacokinetics. In four resistant mouse tumor models of both syngeneic and human xenograft, combination treatment of fluoxetine and doxorubicin generated substantial (P < 0.001) improvements in tumor responses and in survivals (2- to 3-fold). Moreover, fluoxetine reversed MDR at doses that are well below its human safety limits, free of the severe dose-related toxicity, adverse effects, and poor solubility that are obstacles to other chemosensitizers. This low-dose range, together with the findings reported here, indicate that fluoxetine has a high potential to join the arsenal of MDR reversal agents that may reach the clinic. PMID: 15492283 [PubMed - indexed for MEDLINE] __________________ Mom's treatment history (link)