Combination therapy with 2‐difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma

Chen, Yan; Weeks, Reitha S.; Burns, Mark R.; Boorman, David W.; Klein‐Szanto, Andres J.; O’Brien, Thomas G.

doi:10.1002/ijc.21621

Cited by 39 publications

(53 citation statements)

References 17 publications

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“…When considering the mechanism by which polyamines elicit their biological activities on immune and cancer cell functions, inhibition of polyamine uptake by cells seems to be an important target for polyamine-based cancer therapy particularly because inhibition of polyamine synthesis alone failed to produce a favorable effect on cancer treatments in several clinical trials. In addition to inhibiting polyamine synthesis and supply, inhibition of polyamine uptake via the polyamine transporter may have beneficial effects [120,121]. …”

Section: Resultsmentioning

confidence: 99%

The mechanisms by which polyamines accelerate tumor spread

Soda

2011

J Exp Clin Cancer Res

228

167

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Increased polyamine concentrations in the blood and urine of cancer patients reflect the enhanced levels of polyamine synthesis in cancer tissues arising from increased activity of enzymes responsible for polyamine synthesis. In addition to their de novo polyamine synthesis, cells can take up polyamines from extracellular sources, such as cancer tissues, food, and intestinal microbiota. Because polyamines are indispensable for cell growth, increased polyamine availability enhances cell growth. However, the malignant potential of cancer is determined by its capability to invade to surrounding tissues and metastasize to distant organs. The mechanisms by which increased polyamine levels enhance the malignant potential of cancer cells and decrease anti-tumor immunity are reviewed. Cancer cells with a greater capability to synthesize polyamines are associated with increased production of proteinases, such as serine proteinase, matrix metalloproteinases, cathepsins, and plasminogen activator, which can degrade surrounding tissues. Although cancer tissues produce vascular growth factors, their deregulated growth induces hypoxia, which in turn enhances polyamine uptake by cancer cells to further augment cell migration and suppress CD44 expression. Increased polyamine uptake by immune cells also results in reduced cytokine production needed for anti-tumor activities and decreases expression of adhesion molecules involved in anti-tumor immunity, such as CD11a and CD56. Immune cells in an environment with increased polyamine levels lose anti-tumor immune functions, such as lymphokine activated killer activities. Recent investigations revealed that increased polyamine availability enhances the capability of cancer cells to invade and metastasize to new tissues while diminishing immune cells' anti-tumor immune functions.

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Section: Resultsmentioning

confidence: 99%

The mechanisms by which polyamines accelerate tumor spread

Soda

2011

J Exp Clin Cancer Res

228

167

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“…However, murine squamous cell carcinomas, with the exception of aggressive spindle cell carcinomas, show rapid tumor regression following treatment with high doses of DFMO (Chen et al, 2004). In addition, an attempt to achieve sufficient depletion of polyamines by inhibiting not only polyamine biosynthesis but also polyamine uptake has recently been reported to be significantly more effective in causing regression of murine squamous cell carcinomas compared to DFMO alone (Chen et al, 2006). Use of a polyamine uptake inhibitor in this study also permitted the use of lower doses of DFMO to achieve tumor regression and led to a greater decline in tumor polyamine levels compared to that seen using higher doses of DFMO alone (Chen et al, 2006).…”

Section: Polyamine-based Therapy In Skin Cancermentioning

confidence: 72%

“…In addition, an attempt to achieve sufficient depletion of polyamines by inhibiting not only polyamine biosynthesis but also polyamine uptake has recently been reported to be significantly more effective in causing regression of murine squamous cell carcinomas compared to DFMO alone (Chen et al, 2006). Use of a polyamine uptake inhibitor in this study also permitted the use of lower doses of DFMO to achieve tumor regression and led to a greater decline in tumor polyamine levels compared to that seen using higher doses of DFMO alone (Chen et al, 2006). Thus, the effects of DFMO in combination chemotherapy for squamous cell carcinomas remain to be more fully investigated, especially in recurrent or inoperable skin cancer.…”

Section: Polyamine-based Therapy In Skin Cancermentioning

confidence: 99%

Polyamines and nonmelanoma skin cancer

Gilmour

2007

Toxicology and Applied Pharmacology

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Elevated levels of polyamines have long been associated with skin tumorigenesis. Tightly regulated metabolism of polyamines is critical for cell survival and normal skin homeostasis, and these controls are dysregulated in skin tumorigenesis. A key enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC) is upregulated in skin tumors compared to normal skin. Use of transgenic mouse models has demonstrated that polyamines play an essential role in the early promotional phase of skin tumorigenesis. The formation of skin tumors in these transgenic mice is dependent upon polyamine biosynthesis, especially putrescine, since treatment with inhibitors of ODC activity blocks the formation of skin tumors and causes the rapid regression of existing tumors. Although the mechanism by which polyamines promote skin tumorigenesis are not well understood, elevated levels of polyamines have been shown to stimulate epidermal proliferation, alter keratinocyte differentiation status, increase neovascularization, and increase synthesis of extracellular matrix proteins in a manner similar to that seen in wound healing. It is becoming increasingly apparent that elevated polyamine levels activate not only epidermal cells but also underlying stromal cells in the skin to promote the development and progression of skin tumors. The inhibition of polyamine biosynthesis has potential to be an effective chemoprevention strategy for nonmelanoma skin cancer.

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“…The homodimers of putrescine (10) and spermine (15,19) and polymer of spermine (1) have been shown to effectively inhibit PAT. Simple lysine-spermine conjugate (7,46) and lipophilic lysine-spermine (5) also exhibit PAT inhibition activity. 44-Ant-44, the compound shown to have anti-PCP activity in this study, is structurally similar to a spermidine dimer cross-linked by a 9,10-bis-substituted anthraldehyde.…”

Section: Discussionmentioning

confidence: 99%

“…Studies using both ODC (DFMO) and PAT inhibitors to treat PCP are being conducted. This combination therapy is expected to be a more effective PCP treatment, as a synergistic effect has been shown in cancer therapy (5,7). Because of a limited supply of the compound, only one dosage and one treatment condition were tested in the current study.…”

Section: Discussionmentioning

confidence: 99%

Polyamine Transport as a Target for Treatment ofPneumocystisPneumonia

Liao

Phanstiel

Lasbury

et al. 2009

Antimicrob Agents Chemother

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Polyamine levels are greatly increased in alveolar macrophages (AMs) during Pneumocystis pneumonia (PCP), leading to increased production of H 2 O 2 , which causes AMs to undergo apoptosis. One of the mechanisms by which polyamine levels in AMs are elevated is enhanced uptake of exogenous polyamines. In this study, the possibility of targeting polyamine uptake as a treatment for PCP was examined. Pneumocystis pneumonia (PCP) is the leading opportunistic disease in AIDS patients. PCP can be life threatening, as it may cause extensive pulmonary injury, impaired gas exchange, and respiratory failure. The first-line drug for both prophylaxis and treatment of PCP is a combination of trimethoprim and sulfamethoxazole (TMP-SMZ) (40). TMP and SMZ inhibit dihydrofolate reductase and dihydropteroate synthase (DHPS), respectively (18). However, TMP-SMZ may cause adverse effects, such as fever and rash (37), and TMP-SMZ-resistant Pneumocystis strains have emerged (28), probably due to point mutations at codon 55 or 57 of the DHPS gene of Pneumocystis jirovecii (18,41). Clindamycin-primaquine, atovaquone, and pentamidine are alternative therapies for PCP; however, they are also associated with the issues of side effects.Another potential target for treatment of PCP is polyamine synthesis (8,9,14,32,36,39). Polyamines are essential organic compounds for cell growth (20,26). The rate-limiting enzyme of polyamine synthesis is ornithine decarboxylase (ODC), which is usually increased in proliferating cells. ␣-Difluoromethylornithine (DFMO, also known as eflornithine) is a potent ODC inhibitor with low cytotoxicity. DFMO was first developed as an anticancer drug and was shown to be effective for treatment of trypanosomiasis (2,29). It also has activity against Plasmodium falciparum (30), Giardia lamblia (13), Eimeria tenella (16), and Trichomonas vaginalis (47). DFMO has also been used to treat PCP in humans, with success rates ranging from 33 to 57% (14,32,36,38,39). This partial success suggests that targeting polyamine synthesis alone is not sufficient for treatment of PCP.Our recent studies revealed that polyamine levels in alveolar macrophages (AMs) are greatly increased during PCP, resulting in an elevated apoptosis rate and impaired Pneumocystis clearance activity by AMs (23). We also found that the increased intracellular polyamine levels were at least partially due to increased uptake of exogenous polyamines (25). Based on these findings, we hypothesized that polyamine uptake can be a target for treatment of PCP and tested five potential polyamine transport (PAT) inhibitors. Results showed that compound 44-Ant-44 was effective against PCP in a rat model.

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Combination therapy with 2‐difluoromethylornithine and a polyamine transport inhibitor against murine squamous cell carcinoma

Cited by 39 publications

References 17 publications

The mechanisms by which polyamines accelerate tumor spread

The mechanisms by which polyamines accelerate tumor spread

Polyamines and nonmelanoma skin cancer

Polyamine Transport as a Target for Treatment ofPneumocystisPneumonia

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