Abstract
Prooxidative therapy is a well-established concept in infectiology and parasitology, in which prooxidative drugs like artemisinin and metronidazole play a pivotal clinical role. Theoretical considerations and earlier studies have indicated that prooxidative therapy might also represent a promising strategy in oncology. Here, we have investigated a novel class of prooxidative drugs, namely chain-transfer agents, as cytostatic agents in a series of human tumor cell lines in vitro. We have found that different chain-transfer agents of the lipophilic thiol class (like dodecane-1-thiol) elicited half-maximal effective concentrations in the low micromolar range in SY5Y cells (human neuroblastoma), Hela cells (human cervical carcinoma), HEK293 cells (immortalized human kidney), MCF7 cells (human breast carcinoma), and C2C12 cells (mouse myoblast). In contrast, HepG2 cells (human hepatocellular carcinoma) were resistant to toxicity, presumably through their high detoxification capacity for thiol groups. Cytotoxicity was undiminished by hypoxic culture conditions, but substantially lowered after cellular differentiation. Compared to four disparate, clinically used reference compounds in vitro (doxorubicin, actinomycin D, 5-fluorouracil, and hydroxyurea), chain-transfer agents emerged as comparably potent on a molar basis and on a maximum-effect basis. Our results indicate that chain-transfer agents possess a promising baseline profile as cytostatic drugs and should be explored further for anti-tumor chemotherapy.
Highlights
Despite tremendous successes in the last few decades, there is a continuing demand for new lead structures in oncology
The cytostatic activity of the chain-transfer agents was undiminished by hypoxic culture conditions (Figure 3), which is relevant for the potential treatment of solid, hypoxic tumors
Reference cytostatic drugs were purchased from the following suppliers: doxorubicin hydrochloride (Dox; CAS 25316-40-9) was from Cayman Chemicals, Ann Arbor, MI, USA (#15007; purity ≥98%); actinomycin D (Act; CAS 50-76-0) was from Cayman Chemicals (#11421; purity ≥95%); 5-fluorouracil (FU; CAS 51-21-8) was from Sigma-Aldrich
Summary
Despite tremendous successes in the last few decades, there is a continuing demand for new lead structures in oncology. One of the reasons behind this demand is the still sobering survival rate observed with many different types of cancer. The increasing cost of many newer drugs has become a serious concern [2]. To meet these challenges, drug candidates would be interesting that reach beyond the established therapeutic principles [3]. The most difficult task in generating novel and tolerable cytostatic drugs for chemotherapy has been the identification of new biochemical aspects in which tumor cells are substantially and “drugably” different from normal, differentiated cells and normal, but regularly dividing cells such as stem cells
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