Tyrosine Isomers Research Articles

Rapid determination for tyrosine isomers in food based on N-acetyl-L-cysteine/Upconversion nanomaterials target-induced quench by chiral Electrochemiluminescence sensor

Rapid determination of amino acid isomer is very important for the evaluation of the amino acid nutrition in different foods, so a fast and sensitive electrochemiluminescence (ECL) sensor was innovatively fabricated for the determination of tyrosine isomers in foods based on N-Acetyl-L-cysteine/upconversion nanomaterials possessed a good particular selectivity to L-tyrosine. Under the optimal conditions, for L-tyrosine, the limit of detection (LOD) of the sensor for L-tyrosine was 2.87 × 10−6 M, detection range of 5.5 × 10−5–5.5 × 10−3 M, for D-tyrosine, LOD was 2.56 × 10−5 M, detection range was from 5.5 × 10−4 to 5.5 × 10−3 M. The developed chiral sensor was used to determinate the tyrosine isomers in foods successfully, which provided a convenient method to quickly evaluate the nutritional value of amino acids in food.

The rapid separation and characterization of sulfates of tyrosine and its metabolites in reaction mixtures and human urine using a cyclic ion mobility device and mass spectrometry

Ion mobility (IM) separations, especially when combined with mass spectrometry, offer the opportunity for the rapid analysis and characterization of mixtures. However, the limited resolution afforded by many IM systems means that in practice applications may be limited. Here we have employed an IM separation on a high-resolution cyclic IM device with MS/MS to separate and characterize mixtures of sulfated isomers of tyrosine and associated metabolites containing multiple sulfated isoforms present in reaction mixtures. The cIMS device allowed ions, not resolved using a single pass, to be subjected to multiple passes, enabling the resolution of those with similar collision cross sections (CCS). Predicted single pass CCS values calculated for the isomers likely to be present in these mixtures showed only small differences between them, ranging between of between 0.1 – 0.7 % depending on structure. These small differences highlight the high degree of mobility resolution required for separating the isomers. Experimentally different isoforms of tyrosine sulfate and sulfated tyrosine metabolites could be sufficiently resolved via multipass separations (3–35 passes). This degree of separation provided resolving powers of up to 384 CCS/ΔCCS for sulfated dopamine which enabled good MS/MS spectra to be generated. In human urine the presence of a single sulfated form of tyrosine was detected and identified as the O-sulfate after 3 passes based on the synthetic standard. Of the other tyrosine-related sulfates for which synthetic standards had been prepared only dopamine sulfate was detected in this sample.

A chiral sensing platform based on chiral metal-organic framework for enantiodiscrimination of the isomers of tyrosine and tryptophan

Chiral metal–organic framework (ZIF-8) was successfully prepared through a two-step electrodepostion method by using l-histidine (l-His) as the chiral source, and the resultant chiral ZIF-8 (l-His-ZIF-8) was used for enantiodiscrimination of the isomers of tyrosine (Tyr) and tryptophan (Trp). Although the isomers of both Tyr and Trp could be well discriminated by the l-His-ZIF-8 modified electrode, they displayed opposite voltammetric behaviors on the differential pulse voltammograms (ID-Tyr > IL-Tyr; ID-Trp < IL-Trp), which could be explained by density functional theory (DFT). Finally, both the pH and the electrodeposition time were optimized to obtain the highest recognition efficiency of the l-His-ZIF-8 modified electrode toward the isomers of Tyr and Trp.

Serum concentrations of phenylalanine and tyrosine isomers in patients with acute coronary syndrome.

Serum concentrations of phenylalanine and tyrosine isomers in patients with acute coronary syndrome.

Oxidation alters the architecture of the phenylalanyl-tRNA synthetase editing domain to confer hyperaccuracy.

High fidelity during protein synthesis is accomplished by aminoacyl-tRNA synthetases (aaRSs). These enzymes ligate an amino acid to a cognate tRNA and have proofreading and editing capabilities that ensure high fidelity. Phenylalanyl-tRNA synthetase (PheRS) preferentially ligates a phenylalanine to a tRNAPhe over the chemically similar tyrosine, which differs from phenylalanine by a single hydroxyl group. In bacteria that undergo exposure to oxidative stress such as Salmonella enterica serovar Typhimurium, tyrosine isomer levels increase due to phenylalanine oxidation. Several residues are oxidized in PheRS and contribute to hyperactive editing, including against mischarged Tyr-tRNAPhe, despite these oxidized residues not being directly implicated in PheRS activity. Here, we solve a 3.6 Å cryo-electron microscopy structure of oxidized S. Typhimurium PheRS. We find that oxidation results in widespread structural rearrangements in the β-subunit editing domain and enlargement of its editing domain. Oxidization also enlarges the phenylalanyl-adenylate binding pocket but to a lesser extent. Together, these changes likely explain why oxidation leads to hyperaccurate editing and decreased misincorporation of tyrosine. Taken together, these results help increase our understanding of the survival of S. Typhimurium during human infection.

Self-assembled chitosan-sodium alginate composite material for electrochemical recognition of tyrosine isomers

• The CS-SA porous chiral composite was synthesized by electrostatic self-assembly. • The chiral sensor was constructed for electrochemical recognition of Tyr isomers. • The mechanism of chiral recognition was studied using molecular simulation docking. Chitosan-sodium alginate (CS-SA) chiral composite sensing material was prepared by electrostatic self-assembly method. Scanning electron microscope images show that the morphologies of chitosan (CS) and sodium alginate (SA) have changed after self-assembly, which resulted in a new porous network structure. The structure and composition of the chiral composite sensing material were also identified by infrared spectroscopy, thermogravimetric analysis, and X-ray photoelectron spectroscopy. The self-assembled CS-SA chiral composite sensing material was drip-coated on the glass carbon electrode to construct an electrochemical sensing interface. The tested square wave voltammetry curve in the l -tyrosine ( l -Tyr) and d -tyrosine ( d -Tyr) solution presented that CS-SA chiral composite sensing material can specifically bind to l -tyrosine, and the binding force is determined as hydrogen bonding by the method of molecular docking calculation. Although chitosan molecules have abundant chiral sites, glassy carbon electrodes modified with pure CS molecules cannot effectively recognize tyrosine isomers. After being combined with sodium alginate by electrostatic self-assembly, the efficiency of chiral recognition is significantly improved. This experiment opens up a new method for the combination of chitosan with other materials, and at the same time, expands its application on chiral recognition.

Fluorometric discrimination of tyrosine isomers based on the inner filter effect of chiral Au nanoparticles on MoS2 quantum dots

A fluorescent chiral sensor is proposed based on the inner filter effect (IFE) of chiral Au nanoparticles (AuNPs) on MoS2 quantum dots (MoS2 QDs), which can be used for the discrimination of the isomers of tyrosine (Tyr). l-Tyrosine (l-Tyr) can induce obvious agglomeration of the chiral AuNPs, leading to an attenuated IFE of the chiral AuNPs and greatly restored fluorescence of the MoS2 QDs, and thus the enantioselective recognition of the Tyr isomers can be achieved. Also, l-Tyr but not d-Tyr induced agglomeration of the chiral AuNPs is confirmed by the larger association constant between l-Tyr and the chiral sensor.

PCV95 SERUM Phenylalanine and Tyrosine Isomers in ACUTE Coronary Syndrome Patients

PCV95 SERUM Phenylalanine and Tyrosine Isomers in ACUTE Coronary Syndrome Patients

Assessment of serum phenylalanine and tyrosine isomers in patients with ST-segment elevation vs non-ST-segment elevation myocardial infarction.

BackgroundUnder conditions of oxidative stress, hydroxyl radicals can oxidize phenylalanine (Phe) into various tyrosine (Tyr) isomers (meta‐, ortho‐, and para‐tyrosine; m‐, o‐, and p‐Tyr), depending on the location of the hydroxyl group on the oxidized benzyl ring. This study aimed to compare patients with ST‐segment elevation myocardial infarction (STEMI) and non‐STEMI (NSTEMI) and the serum levels of Phe and Tyr isomers at the aortic root and distal to the culprit lesion in both groups.MethodsForty‐four patients participated in the study: 23 with STEMI and 21 with NSTEMI. Arterial blood samples were taken from the aortic root through a guiding catheter and from the culprit vessel segment distal from the primary lesion with an aspiration catheter, during the percutaneous coronary intervention. Serum levels of Phe, p‐Tyr, m‐Tyr, and o‐Tyr were determined using reverse‐phase high‐performance liquid chromatography.ResultsSerum levels of Phe were significantly higher distal to the culprit lesion compared to the aortic root in patients with STEMI. Serum p‐Tyr/Phe and m‐Tyr/Phe concentration ratios were both lower distal to the culprit lesion than at the aortic root in patients with STEMI. There were no statistically significant differences with respect to changes in serum Phe and Tyr isomers distal to the culprit lesion compared to the aortic root in patients with NSTEMI.ConclusionOur data suggest that changes in serum levels of different Tyr isomers can mediate the effects of oxidative stress during myocardial infarction.

Enantioselective electrochemical sensor of tyrosine isomers based on macroporous carbon embedded with sulfato-β-Cyclodextrin

This work reports an enantioselective electrochemical sensor toward tyrosine (Tyr) enantiomers based on macroporous carbon embedded with sulfato-β-cyclodextrin (MPC-SCD) hybrid. First, MPC-SCD hybrid was synthesized via adsorption of sulfato-β-cyclodextrin (SCD) by macroporous carbon (MPC) in aqueous solution, and characterized using transmission electron microscopy (TEM), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FTIR). Subsequently, an enantioselective electrochemical sensor was fabricated by modifying glassy carbon electrode (GCE) with MPC-SCD hybrid, and its electrochemical performances were characterized by electrochemical impedance spectroscopy (EIS) and cyclic voltammograms (CV). Furthermore, the electrochemical sensor was utilized for chiral analysis toward Tyr enantiomers by differential pulse voltammograms (DPV). The peak currents of Tyr enantiomers increased linearly with increasing concentrations over the range of 1–500 μM. In addition, the sensitivity were calculated as 84.59 and 73.02 μA/mM for D-Tyr and L-Tyr, respectively, and the detection limits were 0.20 and 0.26 μM. Furthermore, multiple linear regression (MLR) chemometrics modeling method was used for simultaneously analysis of Tyr enantiomers. The presented sensor could provide a promising protocol for designing novel electrochemical platforms in the field of chiral analysis.

One-step electrodeposition of the MOF@CCQDs/NiF electrode for chiral recognition of tyrosine isomers.

Electrochemical enantiorecognition of tyrosine (Tyr) isomers using a MOF@CCQDs/NiF electrode prepared by electrodepositing a metal-organic framework (MOF) and chiral carbon quantum dots (CCQDs) on Ni foil is reported. MOF@CCQDs/NiF not only shows highly selective, sensitive and quantitative analysis towards Tyr enantiomers but also presents the ability to determine l-Tyr% in racemic mixtures. This proposed that chiral sensors could be considered for practical applications in the field of Tyr related medical recognition.

Tyrosine aminotransferase is involved in the oxidative stress response by metabolizing meta-tyrosine in Caenorhabditis elegans

Under oxidative stress conditions, hydroxyl radicals can oxidize the phenyl ring of phenylalanine, producing the abnormal tyrosine isomer meta-tyrosine (m-tyrosine). m-Tyrosine levels are commonly used as a biomarker of oxidative stress, and its accumulation has recently been reported to adversely affect cells, suggesting a direct role for m-tyrosine in oxidative stress effects. We found that the Caenorhabditis elegans ortholog of tyrosine aminotransferase (TATN-1)-the first enzyme involved in the metabolic degradation of tyrosine-is up-regulated in response to oxidative stress and directly activated by the oxidative stress-responsive transcription factor SKN-1. Worms deficient in tyrosine aminotransferase activity displayed increased sensitivity to multiple sources of oxidative stress. Biochemical assays revealed that m-tyrosine is a substrate for TATN-1-mediated deamination, suggesting that TATN-1 also metabolizes m-tyrosine. Consistent with a toxic effect of m-tyrosine and a protective function of TATN-1, tatn-1 mutant worms exhibited delayed development, marked reduction in fertility, and shortened lifespan when exposed to m-tyrosine. A forward genetic screen identified a mutation in the previously uncharacterized gene F01D4.5-homologous with human transcription factor 20 (TCF20) and retinoic acid-induced 1 (RAI1)-that suppresses the adverse phenotypes observed in m-tyrosine-treated tatn-1 mutant worms. RNA-Seq analysis of F01D4.5 mutant worms disclosed a significant reduction in the expression of specific isoforms of genes encoding ribosomal proteins, suggesting that alterations in protein synthesis or ribosome structure could diminish the adverse effects of m-tyrosine. Our findings uncover a critical role for tyrosine aminotransferase in the oxidative stress response via m-tyrosine metabolism.

Oxidation of phenylalanyl-tRNA synthetase positively regulates translational quality control

Accurate translation of the genetic code is maintained in part by aminoacyl-tRNA synthetases (aaRS) proofreading mechanisms that ensure correct attachment of a cognate amino acid to a transfer RNA (tRNA). During environmental stress, such as oxidative stress, demands on aaRS proofreading are altered by changes in the availability of cytoplasmic amino acids. For example, oxidative stress increases levels of cytotoxic tyrosine isomers, noncognate amino acids normally excluded from translation by the proofreading activity of phenylalanyl-tRNA synthetase (PheRS). Here we show that oxidation of PheRS induces a conformational change, generating a partially unstructured protein. This conformational change does not affect Phe or Tyr activation or the aminoacylation activity of PheRS. However, in vitro and ex vivo analyses reveal that proofreading activity to hydrolyze Tyr-tRNAPhe is increased during oxidative stress, while the cognate Phe-tRNAPhe aminoacylation activity is unchanged. In HPX-, Escherichia coli that lack reactive oxygen-scavenging enzymes and accumulate intracellular H2O2, we found that PheRS proofreading is increased by 11%, thereby providing potential protection against hazardous cytoplasmic m-Tyr accumulation. These findings show that in response to oxidative stress, PheRS proofreading is positively regulated without negative effects on the enzyme's housekeeping activity in translation. Our findings also illustrate that while the loss of quality control and mistranslation may be beneficial under some conditions, increased proofreading provides a mechanism for the cell to appropriately respond to environmental changes during oxidative stress.

D-Amino acids do no inhibit biofilm formation in Staphylococcus sp.

D-amino acids are responsible for cell wall re-modelling in Staphylococcus and are capable of inhibition and mature biofilm disassembly. Staphylococcus aureus and Staphylococcus epidermidis are recognised as recurrent nosocomial pathogens and a common cause of biofilm-associated infections. The combination of amino acids used in the study consisted of d- and l- isomers of tyrosine, methionine, tryptophan and phenylalanine. A semiquantitative microplate crystal violet assay was used to assess the effect of amino acids on biofilm development. Biofilm viability staining using fluorescent microscopy was performed to assess the effect of the amino acid mixtures on biofilm development on submerged surfaces. None of the amino acids when tested individually or as a mixture could reduce biofilm formation. However, at the highest concentration tested 25 mmol 1−1 equimolar D-amino acid mixture of tryptophan, phenylalanine, tyrosine and methionine caused a considerable biofilm inhibition in three Staphylococcus strains. Microscopy analysis showed that initial surface attachment remained unaffected at 25 mmol 1−1 mixture of d-amino acids but bacteria did not proceed to form mature biofilms. This suggests inhibition of protein synthesis or a lack of polysaccharide extracellular adhesin formation as no aggregates were observed. The reported bioactivity of D-amino acid on biofilm development and disassembly has been conflictual. It has been established that D-amino acids are incorporated in the bacterial cell wall suggesting they play a role in the complexity of biofilm lifecycle. However, our study indicates that they play no direct role in the inhibition of biofilm formation in Staphylococcus.

Phase II pharmacokinetics of oral SM-88 in heavily pretreated advanced pancreatic ductal adenocarcinoma (PC).

277 Background: SM88 is an oral tyrosine isomer ( TI) and repurposed drugs (CYP3a4 inducer, mTOR inhibitor, oxidative stress catalyst). This regimen has reported no drug related grade 3, 4 or 5 adverse events (JCO 2013 31: e22095) and potential clinical activity in PC (JCO 2018 36: TPS 4156). PC patients have risk factors for malabsorption and a cachexia syndrome rendering some oral therapies potential unreliable. We present PK data from the completely enrolled first stage of an ongoing dose finding phase II in PC. Methods: Open label randomized TI (control – 230 mg bid vs. experimental - 430 mg bid) along with the lowest approved doses of the other agents. Samples were drawn from four patients at pre-dose and up to six h post dosing on cycle day one for two cycles after a single dose of all four components. Results: Mean age: 71.3 (59 – 80), BMI = 25.3 (21.9 – 28.8) and median three prior chemo lines, two post-pancreas surgery and one s/p RT. There was no evidence that the combination altered the expected PKs at C2. There were no serious drug related adverse events. Favorable RECIST, PERCIST or biomarker activity was documented at both TI dose levels. The PK results of the repurposed drugs were consistent with the published data for these agents, despite the combination use and lower than typical label doses; data will be provided. These results were consistent with previous animal and healthier patient PK of SM88. Conclusions: Single dose C1 and C2 TI PKs are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (supp_6): 1605P) and those previously reported in a healthier population of cancer patients (JCO 2018 36: TPS 4156). Based on these results and PK ones from the repurposed drugs, additional data is being collected in order to define the ongoing phase II expansion cohort dose. SM-88 appears to have predictable PK even in heavily pretreated PC patient with prior radiotherapy and surgery. Clinical trial information: NCT03512756. [Table: see text]

A novel electrochemical chiral sensor for tyrosine isomers based on a coordination-driven self-assembly

Alfa-cyclodextrin (α-CD) based chiral sensing device is proposed for electrochemical recognition of tyrosine (Tyr) isomers. α-CD was first modified with Cu2+, and then the obtained Cu2+-modified α-CD (Cu2-α-CD) was integrated to chitosan (CS) to form a coordination-driven self-assembly. The amino group and phenolic hydroxyl group of Tyr could form three intermolecular H-bonds with the high-energy water molecules confined in the cavity of Cu2-α-CD. The host (self-assembly) −guest (Tyr isomers) interactions are different for D- and L-Tyr due to the opposite steric configurations of the Tyr isomers, resulting in significantly discernable electrochemical differences in both peak currents and peak potentials and consequently effective chiral recognition of Tyr isomers. The temperature-sensitivity and chiral specificity of the proposed self-assembly are also investigated in this work. Finally, the percentage of D-Tyr in a racemic mixture can be accurately predicted with the CS/Cu2-α-CD self-assembly, showing its potential in practical applications.

Phase Ib pharmacokinetics of non-hormonal SM88 in patients with non-metastatic recurrent prostate cancer.

e14061 Background: SM88 is a combination of tyrosine isomers ( TI) and repurposed drugs (modulators of CYP3A4, mTOR, and oxidative stress). This regimen has previously reported non-toxic activity in cancers including prostate (PC) ( J Clin Oncol 2013 31: e22095). We present summary data from a completed Ib trial of non-metastatic recurrent PC (nmPC), an ideal candidate for a well-tolerated, non-androgen based treatment. Methods: This was an open-label safety and PK trial of SM88 in patients with nmPC. Cohort 1 received 230 and cohort 2 - 460 mg/day of TI, along with the lowest available doses of the other 3 agents. Multiple samples were drawn at pre-dose and up to 48 h post dosing from 4 patients after a single TI dose; after a single dose of all 4 components; and after 2 weeks of steady state daily combined dosing (SS). Only cohort 2 results are presented. Results: See table below. Each of the 3 approved drugs had expected PK results that will be provided. There was no evidence that the combination altered the expected PKs at SS. There were no serious drug related adverse events. Favorable biomarker activity was documented at both TI dose levels. Conclusions: Single dose and SS TI results from this completed phase Ib trial are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (suppl_6): 1605P). TI PK results changed transiently with the additional components but returned to desirable levels at SS including a higher Cmax, AUC, and more rapid Tmax, indicating rapid absorption. The PK results (not shown) are consistent with the published data for the approved agents, despite the use of lower than typical label doses. Based on these results, the higher TI dose was chosen for the ongoing phase II expansion cohort in nmPC patients. SM-88 appears to have predictable PK as an effective metabolomic regimen for the treatment of advanced prostate cancer devoid of significant toxicities. [Table: see text]

SMK/SM88 toxicity, efficacy, and patient reported outcomes in metastatic pancreas cancer.

e14060 Background: SMK/SM-88 is a combination of novel tyrosine isomer ( TI) and 3 low dose repurposed agents that are generally recognized as safe for typical use. Its mechanism of action is based on the Warburg effect. It has previously been reported to have clinical benefit with little toxicity in a variety of cancers (J. Clin. Oncol. 2013 31: e22095). We now report on a subset of subjects with pancreas cancer. Methods: Retrospective chart review. Results: Subjects received all four SMK/SM-88 components orally and subcutaneously, consisting of a proprietary altered TI, CYP3a4 inducer, mTOR inhibitor and mitochondrial oxidative stress catalyst, five days per week for a period of six weeks (1 cycle). A total of 11 pancreatic cancers cases were identified. The average age was 63.2 (44-81), 36.4% (4/11) were female. Prior treatment included surgery only (n = 3); chemo only (n = 4); multi-modality therapy (n = 2) and unknown or none (n = 2). Duration on study regimen was 3-57 weeks (mean = 28.5). Clinical benefits documented for all subjects included: 1-3 points improvement in ECOG performance status; 1-5 point mean improvement on EORTC questionnaire (scale 1-7); weight gain (1-5 lbs.); and reduction in pain levels (1-9 points/10 scale) with cessation of all analgesics by the end of cycle 1 in 36% (4/11). Overall reduction in tumor size was seen in 27.3% (3/11) including one CR with PFS of at least 6 months duration, and 2 PRs with one known PFS of 15wks. 72.7% (8/11) had stable disease for 6-61wks. One patient had an overall survival of 23.3 months with no further treatment, and one had an overall survival of 43.2 months. All subjects developed hyperpigmentation. Overall, all subjects tolerated the SMK/SM-88 compounds well. No serious or unexpected adverse events related to the agent have been reported. Conclusions: SMK/SM-88 is a promising treatment for metastatic pancreatic cancer with no significant toxicity. Additional studies are on going in other cancers and confirmatory pancreas investigations are planned.

A phase Ib/II, open-label, dose escalation study to evaluate the safety, pharmacokinetics, and efficacy of SM88 in patients with prostate cancer.

TPS2615 Background: Non-hormonal treatments for biochemically recurrent non-metastatic prostate cancer (nmPC) are limited. SM88 is a novel combination of proprietary tyrosine isomer (TI) and other repurposed agents (CYP3a4 inducer, mTOR inhibitor and catalyst) designed to selectively increase metabolic oxidative stress in cancer cells. Early data reported SM88 activity in solid tumors without significant toxicity (Hoffman et al J Clin Oncol 2013; e22095, Hoffman et al Ann Onc 2016: vi551). Methods: This is an open-label multi-center, dose escalating, dose expansion study in nmPC who have failed or refused androgen deprivation. The study includes a dose escalation phase Ib and dose expansion phase 2. The primary objectives are to determine the effect of SM88 on circulating tumor cells (CTC), and progression-free survival. Secondary objectives are: LDH, bone-specific alkaline phosphatase, urinary N-telopeptide, neutrophyll/llymphocyte ratio, cutaneous hyper-pigmentation correlation, PSA doubling times, safety, and patient reported outcomes. As of Jan ‘17, Phase 1b cohorts 1 and 2, with TI and component PK evaluations, have completed enrollment with adequate numbers to establish the Phase 2 dose without DLT. Phase 2 has begun, with 33 patients planned for at least 6 cycles (@28d) to reach the desired power. This would be followed by a pivotal Phase 3 study in the same group of patients. We propose to conduct a pivotal randomized phase 3 of SM88 in rising PSA, nmPC versus patient’s and clinician’s choice, limited to 2 options i.e. observation or ADT therapy. Inclusion would include doubling time &lt; 9 months, elevated CTCs and recurrent disease after localized curative intent therapy (the same population as our completed Phase I and ongoing phase II). Outcomes will include delay of radiographic PFS, and delay of time to subsequent toxic therapy i.e. cytotoxic systemic chemo and/or radiation therapy. We proposed this pivotal trial will lead to a successful NDA for an indication in this population of patients. Rapid accrual is expected at several institutions because of the urgent need for less toxic alternatives to androgen deprivation therapy.

SM88/SMK non-hormonal therapy in recurrent or untreated prostate cancer.

e16540 Background: Prostate cancer (PC) has a poor prognosis. Androgen deprivation therapy is effective but has unacceptable short and long term side effects. SM88 (modulators of mTOR, mitochondrial stress, CYP3a4 and tyrosine isomers) is a novel combination of anti-cancer therapies with previously reported favorable results yet low toxicity in a heterogeneous group of 30 patients with cancer. We now report on a PC cohort treated with SM88. Methods: Retrospective chart review. Results: Between 2012 and 2014, 6 men with PC were treated with SM88, administered 5 days/week over a 6-week treatment cycle. SM88 consisted of daily oral and subcutaneous injection of the components. The average age was 54 years (range 32-66). Five (83.3%) were Caucasian, 1 (16.7%) was Hispanic. patients with prostate cancer were treated with SM88 daily, Monday-Friday, for between 6 to 31 wks (median 11). Four patients had castrate resistant disease, two declined ADT. One had failed prior chemotherapy (see Table). All subjects were not receiving other therapy. One subject died of disease complications approximately 3 months after starting treatment but only received approximately 20 days of therapy over a 6 week cycle. Three patients had PSA nadir responses of &gt;90% reduction over pretreatment peak levels (see table). Two others had radiographic SD for between 10-14 wks. There were no significant toxicity except cutaneous hyperpigmentation. The duration of responses ranged from 10-114 weeks. Best overall responses included 2 patients with complete biochemical response. Four subjects improved their ECOG score during treatment and 2 had no change. Conclusions: SM-88 appears to be well tolerated and to have anti-tumor activity in prostate cancer without androgen deprivation toxicity. Additional confirmatory prospective studies in prostate are ongoing and planned in other cancers. [Table: see text]