Pancreatic cancer (PC) is known to be highly resistant to chemotherapy. Transporters, which regulate the influx and efflux of substrates across the plasma membrane, may play a role in PC drug resistance. ABC transporters are a large family of transmembrane proteins with diverse physiological functions, several of which play major roles in cancer drug resistance. Given that 90% of PC express a mutant K-ras oncogene and that PC are highly hypoxic, I postulated that constitutive K-ras activation and/or hypoxia may correlate with ABC transporter expression, which in turn may promote drug resistance in PC. Using normal and PC cell lines either overexpressing mutant K-ras or subjected to hypoxic treatment, mRNA expression was profiled for 48 ABC transporters. My findings indicate that expression of mutant K-ras and hypoxic treatment, as well as long-term exposure to chemotherapy, may contribute to the development of drug resistance in PC cells in part by inducing the expression of ABC transporters. Similar to ABC transporters, I investigated whether amino acid transporters would mediate drug resistance in PC. The Xc⁻ amino acid transporter (Xc⁻) mediates cellular uptake of cystine for the biosynthesis of glutathione, a major detoxifying agent. Because the Xc⁻ has been regulates the growth of various cancer cell types, and Xc⁻ is expressed in the pancreas, I postulated that the Xc⁻ may be involved in growth and drug resistance in PC. The Xc⁻ transporter is differentially expressed in normal pancreatic tissues and is overexpressed in PC in vivo. Using PC cell lines, I found that cystine uptake via the Xc⁻ was required for growth and survival in response to oxidative stress, and that expression of the Xc⁻ correlated with gemcitabine resistance. Accordingly, inhibition of Xc⁻ expression via siRNA reduced PC cell proliferation and restored sensitivity to gemcitabine. I also identified the anti-inflammatory drug sulfasalazine as a mixed inhibitor of the Xc⁻, which acts to inhibit cell proliferation via reducing Xc⁻ activity and not by reducing NFKB activity. My findings thus indicate that the Xc⁻ plays a role in PC growth in partby contributing to glutathione synthesis to promote PC cell proliferation, survival, and drug resistance.

Cisplatin is one of the most widely used chemotherapeutic anti-cancer drugs due to its ability to effectively damage DNA and cause cell death. Despite this, cisplatin still suffers from two main drawbacks: toxicity and drug resistance. Many cisplatin-like compounds have been synthesized via traditional methods of drug design but very few have been able to enter clinical trials or even be approved for clinical use. The reason why so many compounds have been rejected is that their reaction mechanisms are rarely understood. By observing and studying the reaction mechanisms of a drug at the molecular level, the reaction can be optimized to enhance its therapeutic effects. The powerful technique of time-resolved pump-probe femtosecond laser spectroscopy was performed by Lu et al. to reveal the extremely high reactivity of cisplatin with weakly-bound electrons, thus providing a deeper understanding of this drug’s therapeutic effects. Taking advantage of this reaction mechanism, a molecular promoter can be identified to amplify the therapeutic efficacy of cisplatin by combination in a synergistic manner. Through cell survival rate measurements, fluorescence microscopic studies to view cell death, cell cycle analysis and DNA fragmentation measurements via flow cytometry, as well as absorption spectroscopic studies, the synergistic effects between cisplatin and a new molecular promoter (PM2A) were measured. This new chemotherapeutic regimen, which was designed based on the electron-transfer reaction mechanism of cisplatin, can be used to decrease the required doses of cisplatin used in the clinic (to effectively reduce its toxic side effects), to circumvent the drug resistance and to improve targeting to cancer cells.

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Poly (adenine diphosphate-ribosyl)ation of a variety of nuclear proteins is the immediate response in most eukaryotic cells to DNA strand breaks. This modification is catalysed' by the chromatin bound enzyme Poly (ADP-ribose) polymerase (PADPRP). The enzyme is thought to be intimately involved in several cellular processes including cell differentiation, gene expression, transformation of oncogenes and repair of DNA damage. As a consequence, inhibitors of PADPRP are able to potentiate the cytotoxicity of many anti-tumour agents whose actions include DNA damage, and as such these inhibitors are potential resistance-modifying agents for use in cancer therapy. In order to probe the active site of the enzyme a series of potential mimics (i) of NAD' were synthesised from readily available 3-hydroxybenzamide. The conformation of the amide bond is considered to be important and for increased potency the amide carbonyl should be anti with respect to the nicotinamide C2-C3 bond. Based on this reported observation a series of novel inhibitors were synthesised, which include a series of benzoxazole-4-carboxamide analogues( ii) and 8-hydroxy-2- (substituted)quinazolin-4-one analogues (iii). The structure of the benzoxazole analogues are such that the amide is anchored into the required conformation by an intramolecular hydrogen bond between the carboxamide N-H and the benzoxazole nitrogen. The benzyloxybenzamide analogues had comparable potency to 3-hydroxybenzamide against PADPRP. However, both the benzoxazole-4-carboxamide and 8-hydroxy quinazolin-4-one series of analogues exhibited outstanding inhibitory activity against PADPRP. The most potent of the benzoxazole-4-carboxamide analogues (ii, R= phenyl) had an IC50 value of 2.1 p. M. Exceptional PADPRP inhibitory activity was observed in the 8-hydroxyquinazolin-4-one (iii) series, where R= CH3 (IC50 = 0.4 μ M) and R= 4-nitrophenyl (IC50 = 0.2 μM). Further in vitro evaluation has shown that 8-hydroxy-2-methylquinazolin-4[3H]-one potentiates cytotoxicity in temozolomide treated cells.

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