Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes

It has been shown that a subset of human cancers, notably, melanoma and hepatocellular carcinoma (HCC) are auxotrophic for arginine (Arg), because they do not express argininosuccinate synthetase (ASS), the rate-limiting enzyme for the biosynthesis of arginine from citrulline. These ASS-negative cancer cells require Arg from extracellular sources for survival. When they are exposed to recombinant Arg-degrading enzymes, e.g. arginine deiminase (ADI) or arginase, they die because of Arg starvation; whereas normal cells which express ASS are able to survive. A pegylated ADI (ADI-PEG20) has been developed for clinical trials for advanced melanoma and HCC; and favorable results have been obtained. ADI-PEG20 treatment induces autophagy in auxotrophic cancer cells leading to cell death. Clinical studies in melanoma patients show that re-expression of ASS is associated with ADI-PEG20 resistance. ADI-PEG20 treatment down-regulates the expression of HIF-1α but up-regulates c-Myc in culture melanoma cells. Induction of ASS by ADI-PEG20 involves positive regulators c-Myc and Sp4 and negative regulator HIF1α. Since both HIF-1α and c-Myc play important roles in cancer cell energy metabolism, together these results suggest that targeted cancer cell metabolism through modulation of HIF-1α and c-Myc expression may improve the efficacy of ADI-PEG20 in treating Arg auxotrophic tumors

Overcoming cisplatin resistance by mTOR inhibitor in lung cancer

BACKGROUND: Cisplatin resistance is complex and involves several different mechanisms. Employing cDNA microarray analysis, we have found that cisplatin resistant cells share the common characteristic of increase in ribosomal proteins and elongation factors. We hypothesize that in order to survive cisplatin treatment, cells have to synthesize DNA repair proteins, antiapoptotic proteins and growth-stimulating proteins. Thus, by blocking the translation of these proteins, one should be able to restore cisplatin sensitivity. We have studied the role of CCI-779, an ester analog of rapamycin which is known to inhibit translation by disabling mTOR, in restoring cisplatin sensitivity in a panel of cisplatin resistant cell lines. We have also determined the role of CCI-779 in P-gp1 and MRP1 mediated resistance. RESULTS: Our data show that CCI-779 possess antiproliferative effects in both cisplatin sensitive and resistant cell lines, but shows no effect in P-gp1 and MRP1 overexpressing cell lines. Importantly, CCI-779 at 10 ng/ml (less that 10% of the growth inhibitory effect) can increase the growth inhibition of cisplatin by 2.5–6 fold. Moreover, CCI-779 also enhances the apoptotic effect of cisplatin in cisplatin resistant cell lines. In these resistant cells, adding CCI-779 decreases the amount of 4E-BP phosphorylation and p-70S6 kinase phosphorylation as well as lower the amount of elongation factor while cisplatin alone has no effect. However, CCI-779 can only reverse P-gp mediated drug resistance at a higher dose(1 ug/ml). CONCLUSION: We conclude that CCI-779 is able to restore cisplatin sensitivity in small cell lung cancer cell lines selected for cisplatin resistance as well as cell lines derived from patients who failed cisplatin. These findings can be further explored for future clinical use. On the other hand, CCI-779 at achievable clinical concentration, has no growth inhibitory effect in P-gp1 or MRP1 overexpressing cells. Furthermore, CCI-779 also appears to be a weak MDR1 reversal agent. Thus, it is not a candidate to use in MDR1 or MRP1 overexpressing cells

Pegylated arginine deiminase: a novel anticancer enzyme agent

Pegylated arginine deiminase (ADI-PEG20) is a novel anticancer enzyme that produces depletion of arginine, which is a nonessential amino acid in humans. Certain tumours, such as malignant melanoma and hepatocellular carcinoma, are auxotrophic for arginine. These tumours that are sensitive to arginine depletion do not express argininosuccinate synthetase, a key enzyme in the synthesis of arginine from citrulline. ADI-PEG20 inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo . Phase I – II trials in patients with melanoma and hepatocellular carcinomas have shown the drug to have antitumour activity and tolerable side effects. Large Phase II trials and randomised, controlled Phase III trials are needed to determine its overall efficacy in the treatment of these malignancies and others

Topoisomerase I inhibitors for the treatment of brain tumors

Patients with primary malignant brain tumors have a poor prognosis. Standard treatment includes surgical resection, radiation therapy and chemotherapy. Topoisomerase I inhibitors such as topotecan and irinotecan (CPT-11) represent one class of chemotherapy drugs that have been used in this disease. Recent clinical trials have shown major antitumor activity in recurrent glioblastoma when adding the antiangiogenesis drug bevacizumab with CPT-11. The combination of targeted agents to topoisomerase I inhibitors represent a novel and promising approach. This review will summarize clinical trials with topoisomerase I inhibitors and discuss new treatment strategies for primary malignant brain tumors

Aminoglutethimide in the management of metastatic breast cancer

Aminoglutethimide (AG) with Dexamethasone has been utilized in 26 patients with metastatic breast cancer who had prior response to hormonal manipulation and/or positive estrogen receptor. Objective tumor response (CR + PR) has been achieved in 13 of 26 patients. Responses were seen in soft tissue, bone, and pleura. Six of 26 patients had stable disease and seven of 26 patients had progressive disease. The median duration of response is 12.8 months. The median survival for the responders has not been reached. Non‐responding patients had a median survival of five months. Side effects were minimal, including mild lethargy, rash, fever, and weight gain. This regimen is well tolerated and can be used effectively in metastatic hormone‐receptor‐positive breast cancer

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure

Arginine deprivation in cancer therapy

There has been an increased and renewed interest in metabolic therapy for cancer, particularly Arg deprivation. The purpose of this review is to highlight recent studies that focus on Arg-dependent malignancies with Arginine (Arg)-degrading enzymes, including arginase and Arg deiminase. New developments in this area include understanding of the role of most significantly downregulated gene regulating amino acid metabolism, argininosuccinate synthetase and its expression and therapeutic relevance in different tumors. Recent studies have also shed light on the mechanism of tumor cell death with Arg deprivation, with arginase and pegylated Arg deiminase. Particularly important is understanding the mechanism of resistance that cancers develop after such drug exposure. Finally, recent clinical trials have been performed or are ongoing to use Arg deprivation as treatment for advanced malignancies. Arg deprivation is a promising approach for the treatment of various malignancies