Pentamidine inhibits prostate cancer progression via selectively inducing mitochondrial DNA depletion and dysfunction

Abstract

Objectives We investigated the anti‐cancer activity of pentamidine, an anti‐protozoal cationic aromatic diamidine drug, in prostate cancer cells and aimed to provide valuable insights for improving the efficacy of prostate cancer treatment. Materials and methods Prostate cancer cell lines and epithelial RWPE‐1 cells were used in the study. Cell viability, wound‐healing, transwell and apoptosis assays were examined to evaluate the influences of pentamidine in vitro. RNA‐seq and qPCR were performed to analyse changes in gene transcription levels upon pentamidine treatment. Mitochondrial changes were assessed by measuring mitochondrial DNA content, morphology, membrane potential, cellular glucose uptake, ATP production and ROS generation. Nude mouse xenograft models were used to test anti‐tumour effects of pentamidine in vivo. Results Pentamidine exerted profound inhibitory effects on proliferation, colony formation, migration and invasion of prostate cancer cells. In addition, the drug suppressed growth of xenograft tumours without exhibiting any obvious toxicity in nude mice. Mechanistically, pentamidine caused mitochondrial DNA content reduction and induced mitochondrial morphological changes, mitochondrial membrane potential dissipation, ATP level reduction, ROS production elevation and apoptosis in prostate cancer cells. Conclusions Pentamidine can efficiently suppress prostate cancer progression and may serve as a novel mitochondria‐targeted therapeutic agent for prostate cancer.

Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans

“…Scaffold-based small molecule libraries are well poised to provide important insights for emerging targets such as the MALAT1 triple helix, as these libraries enable strategic tuning of relevant small molecule properties. For example, the para -substituted diphenylfuran (DPF) diamidine called furamidine, which originates from the promiscuous nucleic acid binder pentamidine ( 24–27 ), has known literature precedence for binding to a variety of nucleic acid structures and has enabled structure–activity relationship studies for therapeutically relevant RNAs ( 28–32 ). Importantly, the affinity and selectivity of DPF derivatives for nucleic acids can be modulated through varying amidine positioning and substituent incorporation through the amidine moieties ( 28 , 31 ).…”

Pentamidine Inhibits Ovarian Cancer Cell Proliferation and Migration by Maintaining Stability of PTEN in vitro

“… 12 As well, pentamidine has been reported as a potent agent to inhibit prostate cancer progression by targeting mitochondria. 7 In addition, in nude mice xenograft experiments, pentamidine is able to dramatically reduce the growth of WM9 human melanoma and M47 Lewis lung carcinoma tumors. 12 , 13 , 15 These studies indicate the potential application of pentamidine in chemotherapy.…”

“…Pentamidine is a positively charged aromatic diamine that has a long history of its involvement in the clinical treatment of African trypanosomiasis, antimonial-resistant leishmaniasis and babesiosis as well as the prophylaxis of pneumocystis carinii pneumonia in acquired immune deficiency syndrome (AIDS) patients for several decades. 7–11 Recently, several reports suggested that pentamidine has antitumor potential. In fact, pentamidine has been shown to have anti-proliferative effects on various human cancer cell types such as melanoma, prostate, ovarian, colon, breast, lung, and cervical cancers in vitro.…”

The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History

“…Diamidines are believed to be minor groove binders and as such bind to the DNA double helix, particularly targeting AT-rich sequences [16][17][18][19], impeding replication and transcription processes in the kinetoplast and/or nucleus. Usually, they accumulate strongly in the trypanosome's single mitochondrion (and mitochondria of cancer cells [20]), the compartmentalisation of these dications being driven by the mitochondrial membrane potential and binding to the kinetoplast DNA (kDNA) (for a schematic of the trypanosome structure, see figure 2). Indeed, fluorescent diamidines light up the kinetoplast within 1 minute of administration, a process that is much delayed in resistant parasites [21].…”

“…Further development to an active (and colourless!) trypanocide was undertaken by Maurice Nicolle and Felix Mesnil at the Institut Pasteur [111] in collaboration with by Wilhelm Röhl and Bernhard Heymann at Bayer [7], who via Afridol Violet (20), the first of the symmetrical ureas of the series, and after synthesis of >1000 of related structures, found 'Bayer 205' in 1916 [112]. This was introduced clinically under the name Germanin, and the formula was kept secret and supplied only to German clinicians, i.e., in German colonial territories [113,114].…”