Prostate Cancer Stem Cell-Targeted Efficacy of a New-Generation Taxoid, SBT-1214 and Novel Polyenolic Zinc-Binding Curcuminoid, CMC2.24

Abstract

BackgroundProstate cancer is the second leading cause of cancer death among men. Multiple evidence suggests that a population of tumor-initiating, or cancer stem cells (CSCs) is responsible for cancer development and exceptional drug resistance, representing a highly important therapeutic target. The present study evaluated CSC-specific alterations induced by new-generation taxoid SBT-1214 and a novel polyenolic zinc-binding curcuminoid, CMC2.24, in prostate CSCs.Principal FindingsThe CD133high/CD44high phenotype was isolated from spontaneously immortalized patient-derived PPT2 cells and highly metastatic PC3MM2 cells. Weekly treatment of the NOD/SCID mice bearing PPT2- and PC3MM3-induced tumors with the SBT-1214 led to dramatic suppression of tumor growth. Four of six PPT2 and 3 of 6 PC3MM2 tumors have shown the absence of viable cells in residual tumors. In vitro, SBT-1214 (100nM-1µM; for 72 hr) induced about 60% cell death in CD133high/CD44+/high cells cultured on collagen I in stem cell medium (in contrast, the same doses of paclitaxel increased proliferation of these cells). The cytotoxic effects were increased when SBT-1214 was combined with the CMC2.24. A stem cell-specific PCR array assay revealed that this drug combination mediated massive inhibition of multiple constitutively up-regulated stem cell-related genes, including key pluripotency transcription factors. Importantly, this drug combination induced expression of p21 and p53, which were absent in CD133high/CD44high cells. Viable cells that survived this treatment regimen were no longer able to induce secondary spheroids, exhibited significant morphological abnormalities and died in 2-5 days.ConclusionsWe report here that the SBT-1214 alone, or in combination with CMC2.24, possesses significant activity against prostate CD133high/CD44+/high tumor-initiating cells. This drug combination efficiently inhibits expression of the majority of stem cell-related genes and pluripotency transcription factors. In addition, it induces a previously absent expression of p21 and p53 (“gene wake-up”), which can potentially reverse drug resistance by increasing sensitivity to anti-cancer drugs.

Multifunctional porous silicon nanoparticles for cancer theranostics

“…Further increase in the SF concentration did not decrease the number of viable PC3-MM2 cells. It has been reported that PC3-MM2 cells treated by paclitaxel (Taxol ® ) retained the cell viability and the number of viable cells was increased until paclitaxel reached a concentration of 10 mM, which caused cytotoxicity and induced about 40% of cell death [49]. Limited cytotoxicity of SF to PC3-MM2 might be due to the aggressive proliferative capability of the PC3-MM2 cells in the cell culture medium with 10% FBS.…”

Nanoemulsion formulation of a novel taxoid DHA-SBT-1214 inhibits prostate cancer stem cell-induced tumor growth

“…The human prostate cancer stem cells (PPT2), prostate adenocarcinoma CSC-enriched cell line was established from the stage pT2c pNX pMX prostate cancer patient and cultured according to well established protocol (10). For cell culture from primary mouse tumors, tumor tissues were mechanically and enzymatically disaggregated into single cell suspension under sterile conditions, rinsed with Hank’s balanced salt solution and incubated for 1.5 hours at 37°C in serum-free RPMI medium 1640 containing 200units/ml Collagenases type II and type IV, 120μg/ml penicillin and 100μg/ml streptomycin.…”

“…Our cell biology research laboratory has established patient-derived ultra-low passage prostate cancer cell line which stably retained the features of being immature and stem-like cells (PPT2 cell line) (10). Previous studies from this laboratory have demonstrated that the CD133 high /CD44 high phenotype of prostate cancer cells showed clear stem cell-related features, including high tumor- and spheroid-initiating capacities, plasticity, and high resistance to standard drugs (11).…”

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

“…Therefore, it appears that CSCs represent the most crucial target in the development of next-generation anticancer drugs. 87,88 …”

“…88 The cancer stem cells upregulate expression of stem-cell-related genes and are likely to form 3D colonospheres. Treatment of these CSCs with 1 for 48 h induced ca.…”