Telomere and microtubule targeting in treatment-sensitive and treatment-resistant human prostate cancer cells.

نویسندگان

  • Bin Zhang
  • Silke Suer
  • Ferenc Livak
  • Samusi Adediran
  • Arvind Vemula
  • Mohammad Afnan Khan
  • Yi Ning
  • Arif Hussain
چکیده

Modulating telomere dynamics may be a useful strategy for targeting prostate cancer cells, because they generally have short telomeres. Because a plateau has been reached in the development of taxane-based treatments for prostate cancer, this study was undertaken to evaluate the relative efficacy of targeting telomeres and microtubules in taxane-sensitive, taxane-resistant, androgen-sensitive, and androgen-insensitive prostate cancer cells. Paclitaxel- and docetaxel-resistant DU145 cells were developed and their underlying adaptive responses were evaluated. Telomere dynamics and the effects of targeting telomeres with sodium meta-arsenite (KML001) (an agent undergoing early clinical trials), including combinations with paclitaxel and docetaxel, were evaluated in parental and drug-resistant cells. The studies were extended to androgen-sensitive LNCaP cells and androgen-insensitive LNCaP/C81 cells. Both P-glycoprotein (Pgp)-dependent and non-Pgp-dependent mechanisms of resistance were recruited within the same population of DU145 cells with selection for drug resistance. Wild-type DU145 cells have a small side population (SP) (0.4-1.2%). The SP fraction increased with increasing drug resistance, which was correlated with enhanced expression of Pgp but not breast cancer resistance protein. Telomere dynamics remained unchanged in taxane-resistant cells, which retained sensitivity to KML001. Furthermore, KML001 targeted SP and non-SP fractions, inducing DNA damage signaling in both fractions. KML001 induced telomere erosion, decreased telomerase gene expression, and was highly synergistic with the taxanes in wild-type and drug-resistant DU145 cells. This synergism extended to androgen-sensitive and androgen-insensitive LNCaP cells under basal and androgen-deprived conditions. These studies demonstrate that KML001 plus docetaxel and KML001 plus paclitaxel represent highly synergistic drug combinations that should be explored further in the different disease states of prostate cancer.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

PI3K and mTOR inhibitor, NVP-BEZ235, is more toxic than X-rays in prostate cancer cells

Background: Radiotherapy and adjuvant androgen deprivation therapy have historically been the first treatment choices for prostate cancer but treatment resistance often limits the capacity to effectively manage the disease. Therefore, alternative therapeutic approaches are needed. Here, the efficacies of radiotherapy and targeting the pro-survival cell signaling components epidermal growth fact...

متن کامل

Knockdown of HSF1 sensitizes resistant prostate cancer cell line to chemotherapy

The treatment of prostate cancer patients usually starts with androgen ablation and followed by chemotherapy; however, in some cases the tumor develops resistant phenotype. Combination therapy is currently regarded as a cornerstone in cancer therapy to overcome the drug resistance. Herein, we investigated the combinatory effect of Docetaxel and Trastuzumab with a novel nanomedicine, BCc1. Also,...

متن کامل

P-14: Effects of Gamma–Ray and Silver Nano Particles on Treatment of Human Prostate Cancer Cell line DU145

Background Prostate cancer is the second most common cancers in the world which causing harms and waste cost. Furthermore more prostate treatments are in effective and lead to male infertility. Purpose of this study was to evaluate the role gamma radiation with silver nano particles in treatment of human prostate cancer cell line in vitro. MaterialsAndMethods Human prostate cancer cell line DU1...

متن کامل

Synergistic Anticancer Effect of Paclitaxel and Noscapine on Human Prostate Cancer Cell Lines

Paclitaxel is the one of the most common chemotherapeutic drugs used for the treatment of prostate cancer. However, its current clinical utility has been limited due to numerous serious side effects and drug resistance. Noscapine is an antitussive opium alkaloid that showed antitumor activity against a variety of cancer while has not exhibited severe side effects. This study investigates the a...

متن کامل

Synergistic Anticancer Effect of Paclitaxel and Noscapine on Human Prostate Cancer Cell Lines

Paclitaxel is the one of the most common chemotherapeutic drugs used for the treatment of prostate cancer. However, its current clinical utility has been limited due to numerous serious side effects and drug resistance. Noscapine is an antitussive opium alkaloid that showed antitumor activity against a variety of cancer while has not exhibited severe side effects. This study investigates the a...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Molecular pharmacology

دوره 82 2  شماره 

صفحات  -

تاریخ انتشار 2012