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

Rich66 · 07-18-2009, 10:38 AM

Links CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells.

Hong SP, Wen J, Bang S, Park S, Song SY.
Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
Accumulating evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth. Recently, there have been efforts to explain drug resistance of cancer cells based on the concept of CSCs having an intrinsic detoxifying mechanism. In the present study, to investigate the role of CSCs in acquiring chemoresistance in pancreatic cancer, gemcitabine-resistant cells were established by exposure to serially escalated doses of gemcitabine in HPAC and CFPAC-1 cells. Gemcitabine-resistant cells were more tumorigenic in vitro and in vivo, and had greater sphere-forming activity than parental cells. After high-dose gemcitabine treatment to eliminate most of the cells, CD44(+) cells proliferated and reconstituted the population of resistant cells.ABC transporter inhibitor verapamil resensitized the resistant cells to gemcitabine in a dose-dependent manner and RNA interference of CD44 inhibited the clonogenic activity of resistant cells. CD44(+)CD24(+)ESA(+) cells remained as a small subset in the resistant cell population. Among ATP-binding cassette (ABC) transporters, which are known as the mechanism of drug resistance in CSCs, ABCB1 (MDR1) was significantly augmented during the acquisition of drug resistance. In human pancreatic cancer samples, CD44 expression was correlated with histologic grade and the patients with CD44-positive tumors showed poor prognosis. These data indicate that cancer stem-like cells were expanded during the acquisition of gemcitabine resistance and in therapeutic application, targeted therapy against the CD44 or ABC transporter inhibitors could be applied to overcome drug resistance in the treatment of pancreatic cancer. (c) 2009 UICC.
PMID: 19598259 [PubMed - as supplied by publisher

Reversal of adriamycin resistance by verapamil in human ovarian cancer

AM Rogan, TC Hamilton, RC Young, RW Klecker Jr, and RF Ozols

The effectiveness of adriamycin in the treatment of ovarian cancer and other human tumors has been limited by the development of drug resistance. Verapamil, a calcium channel blocking agent, completely reversed adriamycin resistance in human ovarian cancer cells with moderate (three- to sixfold) degrees of resistance and partially reversed resistance in highly (150-fold) resistant cells. The potentiating effect of verapamil was due to inhibition of adriamycin efflux in the resistant cells. These results have led to a clinical trial of adriamycin and verapamil in refractory ovarian cancer patients.

07-18-2009, 10:38 AM	#29
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Links CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells. Hong SP, Wen J, Bang S, Park S, Song SY. Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. Accumulating evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth. Recently, there have been efforts to explain drug resistance of cancer cells based on the concept of CSCs having an intrinsic detoxifying mechanism. In the present study, to investigate the role of CSCs in acquiring chemoresistance in pancreatic cancer, gemcitabine-resistant cells were established by exposure to serially escalated doses of gemcitabine in HPAC and CFPAC-1 cells. Gemcitabine-resistant cells were more tumorigenic in vitro and in vivo, and had greater sphere-forming activity than parental cells. After high-dose gemcitabine treatment to eliminate most of the cells, CD44(+) cells proliferated and reconstituted the population of resistant cells.ABC transporter inhibitor verapamil resensitized the resistant cells to gemcitabine in a dose-dependent manner and RNA interference of CD44 inhibited the clonogenic activity of resistant cells. CD44(+)CD24(+)ESA(+) cells remained as a small subset in the resistant cell population. Among ATP-binding cassette (ABC) transporters, which are known as the mechanism of drug resistance in CSCs, ABCB1 (MDR1) was significantly augmented during the acquisition of drug resistance. In human pancreatic cancer samples, CD44 expression was correlated with histologic grade and the patients with CD44-positive tumors showed poor prognosis. These data indicate that cancer stem-like cells were expanded during the acquisition of gemcitabine resistance and in therapeutic application, targeted therapy against the CD44 or ABC transporter inhibitors could be applied to overcome drug resistance in the treatment of pancreatic cancer. (c) 2009 UICC. PMID: 19598259 [PubMed - as supplied by publisher Reversal of adriamycin resistance by verapamil in human ovarian cancer AM Rogan, TC Hamilton, RC Young, RW Klecker Jr, and RF Ozols The effectiveness of adriamycin in the treatment of ovarian cancer and other human tumors has been limited by the development of drug resistance. Verapamil, a calcium channel blocking agent, completely reversed adriamycin resistance in human ovarian cancer cells with moderate (three- to sixfold) degrees of resistance and partially reversed resistance in highly (150-fold) resistant cells. The potentiating effect of verapamil was due to inhibition of adriamycin efflux in the resistant cells. These results have led to a clinical trial of adriamycin and verapamil in refractory ovarian cancer patients.