Telomerase Inhibition, Telomere Shortening, and Cellular Uptake of the Perylene Derivatives PM2 and PIPER in Prostate Cancer Cells

Abstract

Prostate cancer is the second most common cancer among men worldwide, and it is ranked first in the United States and Europe. Since prostate cancer is slow-growing, active surveillance for low-risk cancer has been increasingly supported by various guidelines. Most prostate cancers reactivate telomerase to circumvent the replicative senescence caused by the end replication problem; therefore, telomerase inhibition is potentially useful for the suppression of prostate cancer progression during this active surveillance or for the prevention of cancer recurrence after conventional therapies. In this study, we demonstrated that the perylene derivatives, PM2 and PIPER, could suppress human telomerase reverse transcriptase (hTERT) expression and telomerase activity in the short-term treatment of androgen-dependent prostate cancer cell line LNCaP and the androgen-independent prostate cancer cell line PC3 prostate cancer cells. Long-term treatment with subcytotoxic doses of these compounds in both prostate cancer cells showed telomere shortening and a significant increase in senescent cells. Although the acute cytotoxicity of PM2 was about 30 times higher than that of PIPER in both prostate cancer cells, the cellular uptake of both compounds was comparable as determined by flow cytometry and fluorescent microscopy.

Concepts and principles of self-n-doping in perylene diimide chromophores for applications in biochemistry, energy harvesting, energy storage, and catalysis

“…171 A number of amine and ammonium functionalized PDI derivatives have been found to bind G-quadruplexes, supramolecular structures that form within telomeric and other oncogenic promoter sequences of DNA. [172][173][174] The binding has also been found to be pH dependent, with monomeric species binding in low pH environments to both DNA duplexes and G-quadruplexes, and selective binding of G-quadruplexes with higher order aggregation at higher pH. 175 Amino/ionic PDIs have been found to act as potent competitive binders to these DNA regions over telomerase, and are highly selective to them over other double or single stranded DNA sequences.…”

Hydrosoluble Perylene Monoimide-Based Telomerase Inhibitors with Diminished Cytotoxicity

“… 20 , 23 , 24 In cancer cells, PIPER induces telomere shortening and subsequent cellular senescence in a prolonged time-dependent manner using only subcytotoxic doses. 20 , 23 However, PIPER aggregates at neutral to basic pH solution, which could affect its drug formulation.…”

“… 28 Previously, we found that PM2, a perylene monoimide (PMI) derivative, exhibited better solubility, G4 binding affinity, and telomerase inhibition than PIPER. 20 , 23 Both PM2 and PIPER inhibited telomerase and induced telomere shortening and cellular senescence in lung and prostate cancer cells. 20 , 23 However, the acute cytotoxicity of PM2 was about 20–30 times more than that of PIPER in cancer cells, while the cellular uptake of both compounds was comparable.…”

“… 20 , 23 Both PM2 and PIPER inhibited telomerase and induced telomere shortening and cellular senescence in lung and prostate cancer cells. 20 , 23 However, the acute cytotoxicity of PM2 was about 20–30 times more than that of PIPER in cancer cells, while the cellular uptake of both compounds was comparable. 20 , 23 We hypothesized that PM2 induced cytotoxicity in cancer cells via other mechanisms besides telomerase inhibition and wondered whether one or both side chains of PM2, or PMI in general, were responsible for the increase in its toxicity.…”

“… 20 , 23 However, the acute cytotoxicity of PM2 was about 20–30 times more than that of PIPER in cancer cells, while the cellular uptake of both compounds was comparable. 20 , 23 We hypothesized that PM2 induced cytotoxicity in cancer cells via other mechanisms besides telomerase inhibition and wondered whether one or both side chains of PM2, or PMI in general, were responsible for the increase in its toxicity. Therefore, in this report, we replaced the piperazine side chain of PM2 with the ethylenediamine, to yield PM3, and replaced the N , N -diethylethylenediamine side chain of PM2 with the 1-(2-aminoethyl) piperidine side chain of PIPER, to yield PM5.…”