A Quadruple-Action Platinum(IV) Prodrug with Anticancer Activity Against KRAS Mutated Cancer Cell Lines.

We developed a novel PtIV prodrug that simultaneously releases four different bioactive moieties inside the cancer cell. Its cytotoxicity against monolayer cultures (2D) and spheroid (3D) cancer cells is significantly better than cisplatin. It is 200-450-fold more potent than cisplatin against KRAS mutated pancreatic and colon cancers and is 40-fold more selective towards KRAS mutated cells compared to non-cancerous. This is important since RAS proteins play a role in regulating cell differentiation, proliferation, and survival and KRAS is mutated in 90 % of pancreatic adenocarcinomas, 45 % of colorectal cancers, and 35 % of lung adenocarcinomas. The selectivity index, determined by dividing the IC50 value in non-cancerous cells by that of a cancerous cell line, is two-fold better than cisplatin, attesting to preferential cytotoxicity towards neoplastic cells.

Chemical Composition, Antioxidant and Cytotoxic Activities of Essential Oil of the Inflorescence of Anacamptis coriophora subsp. fragrans (Orchidaceae) from Tunisia.

The chemical composition of the essential oil produced by steam distillation of the inflorescences of naturally growing Anacamptis coriophora (L.) R. M. Bateman, Pridgeon & M. W. Chase subsp.fragrans (Pollini) R. M. Bateman, Pridgeon & M. W. Chase (Orchidaceae) from Kroumiria, north-west Tunisia was studied by GC-MS, which led to the identification of 19 volatile components, representing 97% of the oil. The main constituents were methyl-(E)-p-methoxycinnamate (29.3%), 13-heptadecyn-1-ol (18.6%), 2,5-dimethoxybenzyl alcohol (14.1%) and 4-(1,1,3,3-tetramethylbutyl)-phenol (9.0%). DPPH radical scavenging revealed a weak antioxidant activity. In addition, the antiproliferative effects were evaluated on BxPC3 human pancreatic carcinoma cells and on 2008 human ovarian cancer cells showing significant effect. This is the first report of the chemical composition of essential oils obtained from A. coriophora subsp. fragrans inflorescences for North Africa. Further studies are needed to understand fully the possible mechanism of action behind the cytotoxic activity of the essential oil.

Pt(iv) derivatives of cisplatin and oxaliplatin with phenylbutyrate axial ligands are potent cytotoxic agents that act by several mechanisms of action.

Our study demonstrates that Pt(iv) derivative of cisplatin, with two axial PhB ligands, ctc-[Pt(NH3)2(PhB)2Cl2], is a very potent cytotoxic agent against many different human cancer cell lines and is up to 100 fold more potent than cisplatin, and significantly more potent than the Pt(iv) derivatives of cisplatin with either two hydroxido, two acetato or two valproato ligands. The high potency of this compound (and some others) is due to several factors including enhanced internalization, probably driven by "synergistic accumulation" of both the Pt moiety and the phenylbutyrate, that correlates with enhanced DNA binding and cytotoxicity. ctc-[Pt(NH3)2(PhB)2Cl2] inhibits 60-70% HDAC activity in cancer cells, at levels below the IC50 values of PhB, suggesting synergism between Pt and PhB. Mechanistically, ctc-[Pt(NH3)2(PhB)2Cl2] induces activation of caspases (3 and 9) triggering apoptotic signaling via the mitochondrial pathway. Data also suggest that the antiproliferative effect of ctc-[Pt(NH3)2(PhB)2Cl2] may not depend of p53. Pt(iv) derivatives of cisplatin with either two axial PhB or valproate ligands are more potent than their oxaliplatin analogs. ctc-[Pt(NH3)2(PhB)2Cl2] is significantly more potent than its valproate analog ctc-[Pt(NH3)2(VPA)2Cl2]. These compounds combine multiple effects such as efficient uptake of both Pt and PhB with DNA binding, HDAC inhibition and activation of caspases to effectively kill cancer cells.