Search

Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy., Areas Covered: Triphenylphosphonium cation (TPP + )-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP + -based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies., Expert Opinion: TPP + -based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP + -based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP + -based OXPHOS-inhibiting drugs in cancer prevention and treatment.

Neuroblastoma (NB) is a solid tumor occurring in infancy and childhood. Its high-risk form has currently a survival rate <50%, despite aggressive treatments. This worrying scenario is worsened by drug-induced secondary tumorigenesis and the emergency of drug resistance, calling for the urgent development of new extra-genomic treatments. Triphenyl phosphonium salts (TPPs) are mitochondria-targeting compounds that exert anticancer effects, impair mitochondria functions, and damage DNA at the same time. Despite several biochemical applications, TPP-based bola-amphiphiles self-assembling nanoparticles (NPs) in water have never been tested as antitumor agents. Here, with the aim of developing new antitumor devices to also counteract resistant forms of HR-NB, the anticancer effects of a TPP-based bola-amphiphile molecule have been investigated in vitro for the first time. To this end, we considered the previously synthesized and characterized sterically hindered quaternary phosphonium salt (BPPB). It embodies both the characteristics of mitochondria-targeting compounds and those of bola-amphiphiles. The anticancer effects of BPPB were assessed against HTLA-230 human stage-IV NB cells and their counterpart, which is resistant to etoposide (ETO), doxorubicin (DOX), and many other therapeutics (HTLA-ER). Very low IC50 values of 0.2 µM on HTLA-230 and 1.1 µM on HTLA-ER (538-fold lower than that of ETO) were already determined after 24 h of treatment. The very low cell viability observed after 24 h did not significantly differ from that observed for the longest exposure timing. The putative future inclusion of BPPB in a chemotherapeutic cocktail for HR-NB was assessed by investigating in vitro its cytotoxic effects against mammalian cell lines. These included monkey kidney cells (Cos-7, IC50 = 4.9 µM), human hepatic cells (HepG2, IC50 = 9.6 µM), a lung-derived fibroblast cell line (MRC-5, IC50 = 2.8 µM), and red blood cells (RBCs, IC50 = 14.9 µM). Appreciable to very high selectivity indexes (SIs) have been determined after 24 h treatments (SIs = 2.5–74.6), which provided evidence that both NB cell populations were already fully exterminated. These in vitro results pave the way for future investigations of BPPB on animal models and upon confirmation for the possible development of BPPB as a novel therapeutic to treat MDR HR-NB cells. [ABSTRACT FROM AUTHOR]