The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer.
PHI-443 (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea) is a rationally designed novel thiophene thiourea nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent anti-HIV activity against the wild-type and drug-resistant primary clinical human immunodeficiency virus (HIV-1) isolates. This study examined the potential utility of PHI-443 as a nonspermicidal microbicide for prevention of sexual transmission of HIV. Our goal in this study was to test the effects of PHI-443 on in vivo sperm functions under conditions shown to inactivate viruses in human cells. PHI-443 completely prevented the vaginal transmission of a genotypically and phenotypically drug-resistant HIV-1 isolate in the humanized severe combined immunodeficient (Hu-SCID) mouse model of sexually transmitted AIDS. Exposure of human sperm to PHI-443 at doses 30 000 times higher than those that yield effective concentrations against the AIDS virus had no adverse effect on sperm motility, kinematics, cervical mucus penetrability, or the viability of vaginal and cervical epithelial cells. Exposure of rabbit semen to PHI-443 either ex vivo or in vivo had no adverse impact on in vivo fertilizing ability in the rabbit model. Reproductive indices (i.e., pregnancy rate, embryo implantation, and preimplantation losses) were not affected by pretreatment of rabbit semen with PHI-443. Likewise, intravaginal application of 2% PHI-443 via a self-emulsifying gel at the time of artificial insemination resulted in healthy offspring with no apparent peri- or postnatal repercussions. Repeated intravaginal administration of 0.5%- 2% PHI-443 gel was found to be safe in rabbits and lacked systemic absorption. PHI-443 has clinical potential as a prophylactic broad-spectrum anti-HIV microbicide without contraceptive activity.
Here we report the antiretroviral activity of the experimental nucleoside reverse transcriptase inhibitor (NRTI) compound stampidine in cats chronically infected with feline immunodeficiency virus (FIV). Notably, a single oral bolus dose of 50 or 100 mg of stampidine per kg resulted in a transient >1-log decrease in the FIV load of circulating peripheral blood mononuclear cells in five of six FIV-infected cats and no side effects. A 4-week stampidine treatment course with twice-daily administration of hard gelatin capsules containing 25 to 100 mg of stampidine per kg was also very well tolerated by cats at cumulative dose levels as high as 8.4 g/kg and exhibited a dose-dependent antiretroviral effect. One of three cats treated at the 25-mg/kg dose level, three of three cats treated at the 50-mg/kg dose level, and three of three cats treated at the 100-mg/kg dose level (but none of three control cats treated with placebo pills) showed a therapeutic response, as evidenced by a >1-log reduction in the FIV load in peripheral blood mononuclear cells within 2 weeks. The previously documented in vitro and in vivo antiretroviral activity of stampidine against primary clinical human immunodeficiency virus type 1 isolates with genotypic and/or phenotypic NRTI resistance, together with its favorable animal toxicity profile, pharmacokinetics, and in vivo antiretroviral activity in FIV-infected cats, warrants further development of this promising new NRTI compound.Stavudine (STV) is a pyrimidine nucleoside analogue used in the treatment of human immunodeficiency virus (HIV) infection. It inhibits viral reverse transcriptase (RT), as do zidovudine (ZDV), didanosine, zalcitabine, and lamivudine, which make up the family of nucleoside RT inhibitors (NRTIs). The 5Ј triphosphates of these NRTI, which are generated intracellularly by the action of nucleoside and nucleotide kinases, are potent inhibitors of HIV type 1 (HIV-1) RT (13). The rate-limiting step in the generation of the bioactive STV metabolite STV triphosphate is conversion of STV to its monophosphate derivative (3,13,23). To overcome the dependence of STV on intracellular nucleoside kinase activation, we prepared stampidine (STAMP) HI-113, STV-5Ј-(p-bromophenyl methoxyalaninyl phosphate), a novel aryl phosphate derivative of STV (18,23,25). In preliminary studies, we found that STAMP is substantially more potent than STV at inhibiting HIV-1 replication in thymidine kinase-deficient T cells (23). STAMP was a much more potent anti-HIV agent than STV, and it was active against phenotypically and/or genotypically NRTI-resistant HIV strains for which the 50% inhibitory concentrations (IC 50 s) are in the low nanomolar-to-subnanomolar range (21). Similarly, STAMP inhibited the replication of laboratory HIV-1 strains and primary clinical HIV-1 isolates with non-NRTI (NNRTI) (1) binding site mutations and NNRTI-resistant phenotypes for which the IC 50 s are in the low nanomolar-to-subnanomolar range (21).
BackgroundST-246® is an antiviral, orally bioavailable small molecule in clinical development for treatment of orthopoxvirus infections. An intravenous (IV) formulation may be required for some hospitalized patients who are unable to take oral medication. An IV formulation has been evaluated in three species previously used in evaluation of both efficacy and toxicology of the oral formulation.Methodology/Principal FindingsThe pharmacokinetics of ST-246 after IV infusions in mice, rabbits and nonhuman primates (NHP) were compared to those obtained after oral administration. Ten minute IV infusions of ST-246 at doses of 3, 10, 30, and 75 mg/kg in mice produced peak plasma concentrations ranging from 16.9 to 238 µg/mL. Elimination appeared predominately first-order and exposure dose-proportional up to 30 mg/kg. Short IV infusions (5 to 15 minutes) in rabbits resulted in rapid distribution followed by slower elimination. Intravenous infusions in NHP were conducted at doses of 1 to 30 mg/kg. The length of single infusions in NHP ranged from 4 to 6 hours. The pharmacokinetics and tolerability for the two highest doses were evaluated when administered as two equivalent 4 hour infusions initiated 12 hours apart. Terminal elimination half-lives in all species for oral and IV infusions were similar. Dose-limiting central nervous system effects were identified in all three species and appeared related to high Cmax plasma concentrations. These effects were eliminated using slower IV infusions.Conclusions/SignificancePharmacokinetic profiles after IV infusion compared to those observed after oral administration demonstrated the necessity of longer IV infusions to (1) mimic the plasma exposure observed after oral administration and (2) avoid Cmax associated toxicity. Shorter infusions at higher doses in NHP resulted in decreased clearance, suggesting saturated distribution or elimination. Elimination half-lives in all species were similar between oral and IV administration. The administration of ST-246 was well tolerated as a slow IV infusion.
The irreversible ERBB1/2/4 inhibitor neratinib has been shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET, PDGFRα and mutant RAS proteins via autophagic degradation. Neratinib interacted in an additive to synergistic fashion with the approved PARP1 inhibitor niraparib to kill ovarian cancer cells. Neratinib and niraparib caused the ATM-dependent activation of AMPK which in turn was required to cause mTOR inactivation, ULK-1 activation and ATG13 phosphorylation. The drug combination initially increased autophagosome levels followed later by autolysosome levels. Preventing autophagosome formation by expressing activated mTOR or knocking down of Beclin1, or knock down of the autolysosome protein cathepsin B, reduced drug combination lethality. The drug combination caused an endoplasmic reticulum stress response as judged by enhanced eIF2α phosphorylation that was responsible for reducing MCL-1 and BCL-XL levels and increasing ATG5 and Beclin1 expression. Knock down of BIM, but not of BAX or BAK, reduced cell killing. Expression of activated MEK1 prevented the drug combination increasing BIM expression and reduced cell killing. Downstream of the mitochondrion, drug lethality was partially reduced by knock down of AIF, but expression of dominant negative caspase 9 was not protective. Our data demonstrate that neratinib and niraparib interact to kill ovarian cancer cells through convergent DNA damage and endoplasmic reticulum stress signaling. Cell killing required the induction of autophagy and was cathepsin B and AIF -dependent, and effector caspase independent.
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