Abstract
The impressive impact of cisplatin on cancer on one side and severe side effects, as well as the development of drug resistance during treatment on the other side, were the factors motivating scientists to design and synthesize new more potent analogues lacking disadvantages of cisplatin. Platinum(IV) complexes represent one of the perspective groups of platinum-based drugs. In this review, we summarize recent findings on both in vitro and in vivo effects of platinum(IV) complexes with adamantylamine. Based on a literary overview of the mechanisms of activity of platinum-based cytostatics, we discuss opportunities for modulating the effects of novel platinum complexes through interactions with apoptotic signaling pathways and with cellular lipids, including modulations of the mitochondrial cell death pathway, oxidative stress, signaling of death ligands, lipid metabolism/signaling, or intercellular communication. These approaches might significantly enhance the efficacy of both novel and established platinum-based cytostatics.
Highlights
Platinum-based drugs are widely used anticancer agents with a broad range of antitumor activities
We have demonstrated that LA-9 and LA-12 display a higher hydrophobicity than cisplatin and exert a higher cytotoxicity than satraplatin (JM216) in the in vitro tests on a panel of 14 cancer cell lines of various origin, and a different sensitivity to cisplatin, including both A2780 and A2780cis ovarian cancer cells, breast carcinoma, colon cancer, lung carcinoma, and leukemia cells lines, many of which are refractory to cisplatin treatment [22, 23]
The mitochondriadependent caspase activation cascade has been shown to play a significant role in cisplatin-mediated potentiation of TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in thoracic cancer cells [56]. These results suggest that mitochondria could be a direct target for the development of more refined strategies to enhance the therapeutic effect of TRAIL as an anticancer agent
Summary
Platinum-based drugs are widely used anticancer agents with a broad range of antitumor activities. The enormous efforts of a number of research teams have borne fruit in two derivatives, carboplatin (cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II)) and, more recently, the so-called “third generation” platinum drug oxaliplatin (trans—R,R.cyclohexane-1,2-diammine)oxalatoplatinum(II)) Both compounds are effective in colon cancer treatment and are currently clinically approved worldwide. LA-12 has been evaluated in a panel of preclinical studies including in vitro and in vivo antitumor efficacy and toxicologic and pharmacokinetic studies [20, 21] In both murine ADJ/PC6 plasmacytoma and a human A2780 ovarian carcinoma tumor model, higher in vivo antitumor activity of a single dose as well as of repeated doses was observed, compared to cisplatin and the other platinum(IV) complex—satraplatin (JM216, the first orally administered platinum(IV) drug currently evaluated in clinical trials) [21]. The mechanisms of the effects of these compounds should be further investigated, as several recent studies have demonstrated that LA12 may have unique effects which could be responsible for its high efficiency [24, 26]
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