Complex interactions of lovastatin with 10 chemotherapeutic drugs: a rigorous evaluation of synergism and antagonism

Background Evidence bearing on the role of statins in the prevention and treatment of cancer is confounded by the diversity of statins, chemotherapeutic agents and cancer types included in the numerous published studies; consequently, the adjunctive value of statins with chemotherapy remains uncertain. Methods We assayed lovastatin in combination with each of ten commonly prescribed chemotherapy drugs in highly reproducible in vitro assays, using a neutral cellular substrate, Saccharomyces cerevisiae. Cell density (OD600) data were analyzed for synergism and antagonism using the Loewe additivity model implemented with the Combenefit software. Results Four of the ten chemotherapy drugs – tamoxifen, doxorubicin, methotrexate and rapamycin – exhibited net synergism with lovastatin. The remaining six agents (5-fluorouracil, gemcitabine, epothilone, cisplatin, cyclophosphamide and etoposide) compiled neutral or antagonistic scores. Distinctive patterns of synergism and antagonism, often coexisting within the same concentration space, were documented with the various combinations, including those with net synergism scores. Two drug pairs, lovastatin combined with tamoxifen or cisplatin, were also assayed in human cell lines as proof of principle. Conclusions The synergistic interactions of tamoxifen, doxorubicin, methotrexate and rapamycin with lovastatin – because they suggest the possibility of clinical utility - merit further exploration and validation in cell lines and animal models. No less importantly, strong antagonistic interactions between certain agents and lovastatin argue for a cautious, data-driven approach before adding a statin to any chemotherapeutic regimen. We also urge awareness of adventitious statin usage by patients entering cancer treatment protocols.

Nutrient-use efficiency of Eucalyptus genotypes grown in Luvisol

Superior productivity of genotypes in forest plantations depends on the supply, capture and use-efficiency of resources. In this context, knowledge regarding the nutritional efficiency of Eucalyptus influences farmers and researchers in decision-making and in the management of forest ecosystems. The aim of this research was to estimate nutrient-use efficiency in Eucalyptus genotypes planted in the state of Rio Grande do Sul, Brazil. We evaluated six potential genotypes at 43-month-old stands. Nutrient-use efficiency was calculated using the ratio of biomass and the amount of nutrients for each component of the biomass. Results here presented confirmed that there is synergism and antagonism between nutrients at the shoot level in the Eucalyptus genotypes. For stemwood, E. saligna showed the best utilization efficiency of N, P, K, S, and Mn; and E. urophylla × E. globulus for Mg, B, and Zn. Metabolic pathways control the production of biomass synthesized by each genotype and the differences between genotypes groups were on the basis of their nutrient-use efficiency in the biomass components. Stemwood was the component that showed the highest nutrient-use efficiency, while leaves presented the lowest nutrient-use efficiency. Additionally, our analyses identified how different each Eucalyptus genotype is and these traits may be used for clone allocation according to soil fertility.

Impact of water quality on pesticides and fertilizer compatibility

Mixtures of two or more pesticides are very common in contemporary agriculture. However, changes in their efficacy or biological activity, such as synergism and antagonism, phytotoxicity, persistence, toxicity to non-target organisms, may occur as a consequence. This study was conducted in order to evaluate the compatibility of insecticides (cyantraniliprole - Exirel, chlorantraniliprole - Coragen 20 SC), a fungicide (captan - Merpan 50 WP) and a foliar fertilizer (Folia Stim Mix TE), as well their mixtures, in spray liquids, depending on water quality (well water from two locations in Serbia - Mala Remeta and Cerevic). These products are used to control the most significant peach pests, and as an additional source of nutrients. Water analysis (pH, hardness, electroconductivity, chloride, nitrate, nitrite, ammonia, calcium and iron content) and tests of physico-chemical properties of the spray liquids (pH, suspensibility, dispersibility, surface tension, and electroconductivity) were performed in a laboratory experiment according to standard methods. The physico-chemical properties of the liquids changed depending on water quality and components incorporated in the mixture. However, all tested spray liquids showed consistency and compatibility over a period of 24 hours.

Complex Interactions of Lovastatin with 10 Chemotherapeutic Drugs: A Rigorous Evaluation of Synergism and Antagonism

Background Evidence bearing on the role of statins in the prevention and treatment of cancer is confounded by the diversity of statins, chemotherapeutic agents and cancer types included in the numerous published studies; consequently, the adjunctive value of statins with chemotherapy remains uncertain. Methods We assayed lovastatin in combination with each of ten commonly prescribed chemotherapy drugs in highly reproducible in vitro assays, using an indifferent cellular substrate, Saccharomyces cerevisiae. Cell density (OD600) data were analyzed for synergism and antagonism using the Loewe additivity model implemented with the Combenefit software. Results Four of the ten chemotherapy drugs – tamoxifen, doxorubicin, methotrexate and rapamycin – exhibited net synergism with lovastatin. The remaining six agents (5-fluorouracil, gemcitabine, epothilone, cisplatin, cyclophosphamide and etoposide) compiled neutral or antagonistic scores. Distinctive patterns of synergism and antagonism, often coexisting within the same concentration space, were documented with the various combinations, including those with net synergism scores. Conclusions The interactions of tamoxifen, doxorubicin, methotrexate and rapamycin with lovastatin suggest clinical utility and merit further exploration in cell lines and animal models. No less importantly, strong antagonistic interactions between certain agents and lovastatin argue for a cautious, data-driven approach before adding a statin to chemotherapeutic regimens. We also urge awareness of adventitious statin usage by patients entering cancer treatment protocols.

Differential Accumulation of Innate- and Adaptive-Immune-Response-Derived Transcripts during Antagonism between Papaya Ringspot Virus and Papaya Mosaic Virus

Papaya ringspot virus (PRSV), a common potyvirus infecting papaya plants worldwide, can lead to either antagonism or synergism in mixed infections with Papaya mosaic virus (PapMV), a potexvirus. These two unrelated viruses produce antagonism or synergism depending on their order of infection in the plant. When PRSV is inoculated first or at the same time as PapMV, the viral interaction is synergistic. However, an antagonistic response is observed when PapMV is inoculated before PRSV. In the antagonistic condition, PRSV is deterred from the plant and its drastic effects are overcome. Here, we examine differences in gene expression by high-throughput RNA sequencing, focused on immune system pathways. We present the transcriptomic expression of single and mixed inoculations of PRSV and PapMV leading to synergism and antagonism. Upregulation of dominant and hormone-mediated resistance transcripts suggests that the innate immune system participates in synergism. In antagonism, in addition to innate immunity, upregulation of RNA interference-mediated resistance transcripts suggests that adaptive immunity is involved.

Regimen-dependent synergism and antagonism of treprostinil and vildagliptin in hematopoietic cell transplantation

The cell dose in umbilical cord blood units is a major determinant for the outcome of hematopoietic cell transplantation. Prostaglandin analogs and dipeptidylpeptidase-4 (DPP4/CD26)-inhibitors enhance the ability of hematopoietic stem cells (HSCs) to reconstitute hematopoiesis. Here we explored the synergism between treprostinil, a stable prostaglandin agonist, and the DPP4/CD26-inhibitor vildagliptin. The combination of treprostinil and forskolin caused a modest but statistically significant increase in the surface levels of DPP4/CD26 on hematopoietic stem and progenitor cells (HSPCs) derived from murine bone and human cord blood. Their migration towards stromal cell-derived factor-1 (SDF-1/CXCL12) was enhanced, if they were pretreated with treprostinil and forskolin, and further augmented by vildagliptin. Administration of vildagliptin rescued 25% of lethally irradiated recipient mice injected with a limiting number of untreated HSPCs, but 90 to 100% of recipients injected with HSPCs preincubated with treprostinil and forskolin. The efficacy of vildagliptin surpassed that of treprostinil (60% rescue). Surprisingly, concomitant administration of vildagliptin and treprostinil resulted in poor survival of recipients indicating mutual antagonism, which was recapitulated when homing of and colony formation by HSPCs were assessed. These observations of regimen-dependent synergism and antagonism of treprostinil and vildagliptin are of translational relevance for the design of clinical trials. Key messages Pretreatment with treprostinil increases surface levels of DPP4/CD26 in HSPCs. Vildagliptin enhances in vitro migration of pretreated HSPCs. Vildagliptin enhances in vivo homing and engraftment of pretreated HSPCs. Unexpected mutual antagonism in vivo by concomitant administration of vildagliptin and treprostinil.