Biomedical subjects

Varsha Gandhi

Publications and source records attributed to Varsha Gandhi.

At least 19 recordsLinked to original sources

PubMed2006

The growth factor fusion construct containing B-lymphocyte stimulator (BLyS) and the toxin rGel induces apoptosis specifically in BAFF-R-positive CLL cells.

The cytokine B lymphocyte stimulator (BLyS) mediates its effect through cell-surface receptors BAFF-R, TACI, and BCMA. BLyS receptors are expressed only on B cells and not present in other normal cells including normal T lymphocytes. Chronic lymphocytic leukemia (CLL) is a B-cell disease and CLL lymphocytes express BLyS receptors. Gelonin, a type 1 ribosome-inactivating toxin, lacks cell membrane binding domain and hence is nontoxic to intact cells. We generated a construct of recombinant gelonin (rGel) fused to BLyS to specifically target quiescent B-CLL lymphocytes. The construct rGel/BLyS specifically binds and internalizes through BAFF-R into CD19(+) B-CLL lymphocytes and induces apoptosis at nanomolar concentrations. In contrast, rGel alone was not able to internalize into these leukemic lymphocytes. Mechanistically, the rGel/BLyS construct inhibits protein synthesis with an IC(50) of less than 3 nM compared with more than 5000 nM for rGel toxin alone. This rGel/BLyS-mediated decrease in protein synthesis was associated with a decline in short-lived proteins such as MCL-1 and XIAP, the 2 survival proteins in B-CLL. There was a strong relationship between a decrease in these proteins and the cleavage of PARP, a hallmark feature of apoptosis. Taken together, these data suggest that the rGel/BLyS fusion toxin may have potential therapeutic efficacy for B-CLL patients.

Antigens, CD19↗

PubMed2006

A sequential blockade strategy for the design of combination therapies to overcome oncogene addiction in chronic myelogenous leukemia.

Some tumors are dependent on the continued activity of a single oncogene for maintenance of their malignant phenotype. The best-studied example is the Bcr-Abl fusion protein in chronic myelogenous leukemia (CML). Although the clinical success of the Abl kinase inhibitor imatinib against chronic-phase CML emphasizes the importance of developing therapeutic strategies aimed at this target, resistance to imatinib poses a major problem for the ultimate success of CML therapy by this agent. We hypothesized a sequential blockade strategy that is designed to decrease the expression of the Bcr-Abl protein, with the goal of complementing the action of imatinib on kinase activity. In this study, flavopiridol, an inhibitor of transcription, homoharringtonine (HHT), a protein synthesis inhibitor, and imatinib were used singly and in combination against the Bcr-Abl-positive human CML cell line K562. Flavopiridol alone inhibited phosphorylation of the RNA polymerase II COOH-terminal domain, specifically reduced RNA polymerase II-directed mRNA synthesis, and decreased the Bcr-Abl transcript levels. HHT inhibited protein synthesis and reduced the Bcr-Abl protein level. Imatinib directly inhibited the kinase activity of Bcr-Abl. The combinations of flavopiridol and HHT and flavopiridol and imatinib synergistically decreased clonogenicity as evaluated by the median-effect method. Greater synergy was observed when HHT and imatinib were given sequentially compared with simultaneous administration. Imatinib-resistant Ba/F3 cells that were transfected to express the E255K and T315I mutations of Bcr-Abl were not cross-resistant to flavopiridol and HHT. These results provided a rationale for the combination of inhibitors of transcription and/or translation with specific kinase inhibitors.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Clinical and pharmacokinetic study of clofarabine in chronic lymphocytic leukemia: strategy for treatment.

PURPOSE: Based on its mechanistic similarity to fludarabine and cladribine and the success of these analogues for treatment of chronic lymphocytic leukemia (CLL), we hypothesized that clofarabine would be effective for indolent leukemias. The present study was conducted to determine the efficacy and cellular pharmacology during clinical trials of single-agent clofarabine in CLL. EXPERIMENTAL DESIGN: Previously treated patients with relapsed/refractory CLL were eligible for this study. Clofarabine was infused over 1 hour daily for 5 days. Most patients received 3 or 4 mg/m2/d x 5 days, whereas the other two were treated with 15 mg/m2/d x 5 days. Clinical outcome and associated pharmacologic end points were assessed. RESULTS: Myelosuppression limited the maximum tolerated dose of clofarabine to 3 mg/m2/d on this schedule. Cellular pharmacokinetic studies showed a median clofarabine triphosphate concentration in CLL lymphocytes of 1.5 micromol/L (range, 0.2-2.3 micromol/L; n = 9). In the majority of cases, >50% of the analogue triphosphate was present 24 hours after infusion, indicating prolonged retention of the triphosphate in CLL cells. Although cytoreduction was observed, no patients achieved a response. In vitro clofarabine incubation of leukemic lymphocytes from 29 CLL patients showed that clofarabine monophosphate accumulated to a higher concentration compared with the triphosphate. Nonetheless, the triphosphate increased in a dose-dependent fashion and upon successive clofarabine infusions, suggesting benefit from greater doses given at less frequent intervals. CONCLUSION: Levels of clofarabine triphosphate at higher doses and prolonged maintenance of clofarabine triphosphate in leukemic lymphocytes provide a rationale to treat CLL in a weekly clofarabine schedule.

Adenine Nucleotides↗

PubMed2006

Intracellular nucleotides act as critical prosurvival factors by binding to cytochrome C and inhibiting apoptosome.

Cytochrome c (CC)-initiated Apaf-1 apoptosome formation represents a key initiating event in apoptosis. This process can be reconstituted in vitro with the addition of CC and ATP or dATP to cell lysates. How physiological levels of nucleotides, normally at high mM concentrations, affect apoptosome activation remains unclear. Here we show that physiological levels of nucleotides inhibit the CC-initiated apoptosome formation and caspase-9 activation by directly binding to CC on several key lysine residues and thus preventing CC interaction with Apaf-1. We show that in various apoptotic systems caspase activation is preceded or accompanied by decreases in overall intracellular NTP pools. Microinjection of nucleotides inhibits whereas experimentally reducing NTP pools enhances both CC and apoptotic stimuli-induced cell death. Our results thus suggest that the intracellular nucleotides represent critical prosurvival factors by functioning as natural inhibitors of apoptosome formation and a barrier that cells must overcome the nucleotide barrier to undergo apoptosis cell death.

Apoptosis↗

PubMed2006

Forodesine, an inhibitor of purine nucleoside phosphorylase, induces apoptosis in chronic lymphocytic leukemia cells.

Purine nucleoside phosphorylase (PNP) deficiency in humans results in T lymphocytopenia. Forodesine, a potent inhibitor of PNP, was designed based on the transition-state structure stabilized by the enzyme. Previous studies established that forodesine in the presence of deoxyguanosine (dGuo) inhibits the proliferation of T lymphocytes. A phase 1 clinical trial of forodesine in T-cell malignancies demonstrated significant antileukemic activity with an increase in intracellular dGuo triphosphate (dGTP). High accumulation of dGTP in T cells may be dependent on the levels of deoxynucleoside kinases. Because B-cell chronic lymphocytic leukemia (B-CLL) cells have high activity of deoxycytidine kinase (dCK), we hypothesized that these lymphocytes would respond to forodesine. This postulate was tested in primary lymphocytes during in vitro investigations. Lymphocytes from 12 patients with CLL were incubated with forodesine and dGuo. These CLL cells showed a wide variation in the accumulation of intracellular dGTP without any effect on other deoxynucleotides. This was associated with DNA damage-induced p53 stabilization, phosphorylation of p53 at Ser15, and activation of p21. The dGTP accumulation was related to induction of apoptosis measured by caspase activation, changes in mitochondrial membrane potential, and PARP cleavage. Based on these data, a phase 2 clinical trial of forodesine has been initiated for CLL patients.

Antineoplastic Agents↗

PubMed2006

Quadriceps femoris electromyogram during concentric, isometric and eccentric phases of fatiguing dynamic knee extensions.

The objective of this study was to examine the superficial quadriceps femoris (QF) muscle electromyogram (EMG) during fatiguing knee extensions. Thirty young adults were evaluated for their one-repetition maximum (1RM) during a seated, right-leg, inertial knee extension. All subjects then completed a single set of repeated knee extensions at 50% 1RM, to failure. Subjects performed a knee extension (concentric phase), held the weight with the knee extended for 2s (isometric phase), and lowered the weight in a controlled manner (eccentric phase). Raw EMG of the vastus medialis (VM), vastus lateralis (VL) and rectus femoris (RF) muscles were full-wave rectified, integrated and normalized to the 1RM EMG, for each respective phase and repetition. The EMG median frequency (f(med)) was computed during the isometric phase. An increase in QF muscle EMG was observed during the concentric phase across the exercise duration. VL EMG was greater than the VM and RF muscles during the isometric phase, in which no significant changes occurred in any of the muscles across the exercise duration. A significant decrease in EMG across the exercise duration was observed during the eccentric phase, with the VL EMG greater than the VM and RF muscles. A greater decrease in VL and RF muscle f(med) during the isometric phase, than the VM muscle, was observed with no gender differences. The findings demonstrated differential recruitment of the superficial QF muscle, depending on the contraction mode during dynamic knee extension exercise, where VL muscle dominance appears to manifest across the concentric-isometric-eccentric transition.

Adaptation, Physiological↗

PubMed2006

Nelarabine.

Explore the source record for details and available documents.

Antineoplastic Agents↗

PubMed2006

Clofarabine and nelarabine: two new purine nucleoside analogs.

PURPOSE OF REVIEW: Both clofarabine and nelarabine recently received an accelerated approval by the US Food and Drug Administration for use in refractory or relapsed pediatric acute lymphoblastic leukemia and in refractory-relapsed T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma. Both drugs have been studied for their metabolism and mechanisms of action in preclinical investigations and for their efficacy in clinical trials. This review will summarize these investigations and will suggest future plans with these nucleoside analogs. RECENT FINDINGS: Clofarabine and nelarabine were designed based on preclinical and clinical findings with other nucleoside analogs or normal deoxynucleotides such as dGTP. Studies in cell lines have demonstrated that triphosphate is the active metabolite for both these purine nucleoside analogs. Pharmacokinetic and pharmacodynamic investigations during clinical trials have verified the importance of triphosphate levels in achieving clinical responses. Several phase I and II clinical explorations have suggested the utility of clofarabine in acute leukemias and nelarabine in T-cell diseases. Dose-limiting toxicities were nonhematologic: hepatotoxicity for clofarabine and neurotoxicity for nelarabine. SUMMARY: Clofarabine is the first deoxyadenosine analog that shows promise in adult and pediatric acute leukemias without untoward toxicity. Nelarabine, as expected from its design, is a drug that may be directed to T-cell diseases.

Adenine Nucleotides↗

PubMed2006

Relationship between hip and knee strength and knee valgus during a single leg squat.

The purpose of this study was to determine the relationship between hip and knee strength, and valgus knee motion during a single leg squat. Thirty healthy adults (15 men, 15 women) stood on their preferred foot, squatted to approximately 60 deg of knee flexion, and returned to the standing position. Frontal plane knee motion was evaluated using 3-D motion analysis. During Session 2, isokinetic (60 deg/sec) concentric and eccentric hip (abduction/adduction, flexion/extension, and internal/external rotation) and knee (flexion/extension) strength was evaluated. The results demonstrated that hip abduction (r2=0.13), knee flexion (r2=0.18), and knee extension (r2=0.14) peak torque were significant predictors of frontal plane knee motion. Significant negative correlations showed that individuals with greater hip abduction (r=-0.37), knee flexion (r=-0.43), and knee extension (r=-0.37) peak torque exhibited less motion toward the valgus direction. Men exhibited significantly greater absolute peak torque for all motions, excluding eccentric internal rotation. When normalized to body mass, men demonstrated significantly greater strength than women for concentric hip adduction and flexion, knee flexion and extension, and eccentric hip extension. The major findings demonstrate a significant role of hip muscle strength in the control of frontal plane knee motion.

Adult↗

PubMed2006

Glucocorticoid receptor transcriptional isoforms and resistance in multiple myeloma cells.

Although glucocorticoids play an important role in the treatment of multiple myeloma, some patients do not respond or develop resistance. The glucocorticoid receptor (GR), a single gene, mediates the effects of glucocorticoids. Using a model system of a multiple myeloma cell line sensitive to glucocorticoids and its early and late resistant variants, we have analyzed mutations in the GR gene, detected the presence of different transcriptional isoforms, quantified their levels of expression, and identified the promoters that regulate their expression. Levels of GR transcripts were comparable with the expression of total GR protein. Development of resistance correlates with an overall reduction in GR mRNA levels. This decrease in GR levels is neither due to mutation of the gene nor due to methylation. GRalpha is the predominant isoform in the sensitive cell line decreasing in expression in the early resistant cells and virtually undetectable in late resistant cells. GR-P is expressed at equivalent levels in both sensitive and early resistant cells, whereas in the late resistant cells, GR-P is the predominant isoform. GR-A is only expressed in the early resistant cell line. GRbeta is the least expressed isoform in all cell lines. Interestingly, the level of expression of exon 1-exon 2 RNA fragments remains similar in sensitive and resistant cell lines. Resistant cells became sensitive to glucocorticoids after GRalpha transfection. In conclusion, we show different patterns of expression of the GR isoforms and provide evidence that a decline in the expression of GRalpha may be associated with development of resistance.

Cell Line, Tumor↗

PubMed2006

Novel purine nucleoside analogues for T-cell-lineage acute lymphoblastic leukaemia and lymphoma.

Purine nucleoside phosphorylase (PNP) deficiency is a rare, inherited immunodeficiency disorder in which the specific molecular defect was identified. Clinically, a lack of PNP manifests as profound T-cell deficiency with minor or variable changes in the humoral system. Biochemically, the absence of PNP results in an increase in plasma deoxyguanosine (dGuo) and a T-cell-specific increase in intracellular deoxyguanosine triphosphate (dGTP). This observation has been the impetus for the search for either inhibitors of the enzyme or PNP-resistant dGuo analogues as potential anti-T-cell-lineage agents over the past 30 years. Forodesine (an inhibitor of PNP) and nelarabine (a PNP-resistant dGuo analogue) proved to be T-cell selective when tested in clinic. This review summarises the preclinical, clinical and pharmacokinetic investigations with these novel agents.

Adult↗

PubMed2005

Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial.

Chk1 and Akt signaling facilitate survival of cells treated with nucleoside analogues. Activation of Chk1 in response to cytarabine (ara-C) induced an S-phase checkpoint characterized by the inhibition of Cdk2, cell cycle arrest, no change in constitutively active Akt, or low-stress kinase signaling in ML-1 cells. However, inhibition of Chk1 by UCN-01 in S-phase-arrested cells resulted in an abrogation of the checkpoint, inhibition of Akt, activation of JNK, and a rapid induction of apoptosis. Similarly, primary acute myelogenous leukemia (AML) blasts exposed to ara-C and UCN-01 demonstrated a selective loss in cloning potential when compared with normal progenitors. Therefore, we evaluated a pilot clinical trial of ara-C in combination with UCN-01 in patients with relapsed AML. Blasts from some patients demonstrated a previously activated Chk1-Cdk2 DNA damage response pathway that decreased during therapy. Constitutively phosphorylated Akt kinase declined on addition of UCN-01 to the ara-C infusion, an action accompanied by an activation of JNK and reduction in absolute AML blast counts. Thus, use of UCN-01 in combination with ara-C decreases Chk1 phosphorylation, inhibits the Akt survival pathway, and activates JNK during the course of therapy, offering a rationale for the cytotoxic action of this combination during AML treatment.

Adolescent↗

PubMed2005

Mechanisms of cell death of chronic lymphocytic leukemia lymphocytes by RNA-directed agent, 8-NH2-adenosine.

PURPOSE: To determine if RNA-directed nucleoside analogue, 8-NH(2)-adenosine, induces cell death and if that is accompanied with transcription inhibition of the key survival factors of chronic lymphocytic leukemia (CLL) cells. EXPERIMENTAL DESIGN: Primary lymphocytes from CLL patients were incubated with 10 micromol/L 8-NH(2)-adenosine for 2, 4, and 6 or 8 hours. The accumulation of analogue triphosphate and the decline in endogenous ATP pool were analyzed by high-performance liquid chromatography. Inhibition of global RNA and protein synthesis was measured and correlated with specific decline in transcript and protein levels of MCL-1, XIAP, and BCL-2, the key survival factors of CLL. These biochemical and molecular end points were related to cell death of these quiescent lymphocytes. RESULTS: In vitro incubations of CLL lymphocytes with 8-NH(2)-adenosine resulted in rapid but heterogeneous accumulation of 8-NH(2)-ATP (390-680 micromol/L), with a concomitant decline in endogenous ATP (median, >50% by 4 hour). Global RNA synthesis was decreased in all samples and was associated with a decline in MCL-1, XIAP, and BCL-2 transcripts. There was a parallel decrease in the protein level of MCL-1 and XIAP but not BCL-2. These biochemical changes were accompanied by apoptosis. CONCLUSION: The evidence of CLL cell death with complementary changes in the expression of survival proteins provides a molecular rationale for using 8-NH(2)-adenosine as a therapeutic agent for this indolent leukemia.

Adenosine↗

PubMed2005

A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine).

The discovery of purine nucleoside phosphorylase (PNP) deficiency and T lymphocytopenia suggested that inhibition of this enzyme could serve as a therapeutic target. Inhibitors of PNP failed until structure-based synthesis of immucillin-H (BCX-1777, forodesine), a transition-state analog of PNP. The picomolar potency for PNP, T cell-selective cytotoxicity, and animal studies provided the rationale for use of forodesine in T-cell malignancies. Five patients were treated with an intravenous infusion of forodesine (40 mg/m2) on day 1; treatment continued on day 2; forodesine was administered every 12 hours for an additional 8 doses. Plasma and cellular pharmacokinetics and pharmaco-dynamics were investigated. Median peak level of forodesine (5.4 microM) was achieved at the end of infusion. This level was sufficient to increase plasma 2'-deoxyguanosine (dGuo) concentrations in all patients. Intracellular deoxyguanosine triphosphate (dGTP) increased by 2- to 40-fold in 4 of 5 patients (8 of 9 courses) and correlated with antileukemia activity in 4 patients. However, objective responses were not observed. This was the first clinical study in humans to demonstrate the plasma pharmacokinetics and the pharmacodynamic effectiveness of the PNP inhibitor, forodesine; however, regrowth of leukemia cells in the blood and marrow after course 1 suggested that a different therapeutic schedule should be considered for future studies.

Adult↗

PubMed2005

2-Chlorodeoxyadenosine and cytarabine combination therapy for idiopathic hypereosinophilic syndrome.

BACKGROUND: Hypereosinophilic syndrome (HES) is a rare, disabling, and incurable disease. In this study, a combination of 2-chlorodeoxyadenosine (2-CdA) and cytosine arabinoside (ara-C) chemotherapy was evaluated in patients with HES. METHODS: Nine patients with HES were treated with ara-C (1 g/m(2)) given intravenously over 2 hours at 0 hours, 48 hours, 72 hours, 96 hours, and 120 hours; and 2-CdA (12 mg/m(2) per day) was given as a continuous intravenous infusion over 5 days starting at 24 hours. A second course of the same therapy was administered in patients who had a response. RESULTS: All patients had signs and symptoms of end-organ involvement. The median time from diagnosis to therapy was 25 months. Seven patients had received prior therapies. Five patients (55%) achieved a complete remission (CR), 1 after receiving 2 courses of therapy. Elimination of eosinophilia was accompanied by the resolution of symptoms. The median disease-free survival and overall survival after the diagnosis for patients who achieved CR was 26 months and 44 months, respectively. Treatment was tolerated well. Febrile neutropenia occurred in 28% of the 14 courses that were given. The median time to recovery from neutropenia and thrombocytopenia was 17 days and 39 days, respectively. CONCLUSIONS: The combined 2-CdA and ara-C chemotherapy regimen had activity in patients with HES.

Adolescent↗

PubMed2005

Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death.

Flavopiridol is active against chronic lymphocytic leukemia (CLL) cells in vitro and in the treatment of advanced stage disease, but the mechanisms of these actions remain unclear. Originally developed as a general cyclin-dependent kinase inhibitor, flavopiridol is a potent transcriptional suppressor through the inhibition of positive transcription elongation factor b (P-TEFb; CDK9/cyclin T). P-TEFb phosphorylates the C-terminal domain (CTD) of RNA polymerase II to promote transcriptional elongation. Because most CLL cells are not actively cycling, and their viability is dependent upon the continuous expression of antiapoptotic proteins, we hypothesized that flavopiridol induces apoptosis in CLL cells through the transcriptional down-regulation of such proteins. This study demonstrated that flavopiridol inhibited the phosphorylation of the CTD of RNA polymerase II in primary CLL cells and reduced RNA synthesis. This was associated with a decline of the transcripts and the levels of short-lived antiapoptotic proteins such as myeloid cell leukemia 1 (Mcl-1), and resulted in the induction of apoptosis. The B-cell lymphoma 2 (Bcl-2) protein level remained stable, although its mRNA was consistently reduced, suggesting that the outcome of transcriptional inhibition by flavopiridol is governed by the intrinsic stability of the individual transcripts and proteins. The dependence of CLL-cell survival on short-lived oncoproteins may provide the biochemical basis for the therapeutic index in response to flavopiridol.

Antineoplastic Agents↗

PubMed2005

The role of clofarabine in hematologic and solid malignancies--development of a next-generation nucleoside analog.

Clofarabine is a new-generation nucleoside analog that has been synthesized to combine the most favorable pharmacokinetic properties of its congeners fludarabine and cladribine. In addition to inhibition of DNA polymerases and DNA synthesis, clofarabine acts as a strong inhibitor of ribonucleotide reductase (RnR), an enzyme involved in regulating intracellular deoxynucleotide pools, and has a high affinity to the enzyme deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation.A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) data base and from abstracts based on the publication of meeting materials. Although it was synthesized early in the 1980s, the development of clofarabine was stalled until 1993, when, through efforts at The University of Texas M. D. Anderson Cancer Center, animal toxicology studies were conducted, and the first Phase I study was initiated in patients with hematologic and solid malignancies. Since then, clofarabine has demonstrated single-agent antitumor activity in pediatric and adult acute leukemias. By way of its unique metabolic properties, clofarabine also has lent itself to biochemical modulation strategies with other nucleoside analogs, such as cytarabine. Combinations of clofarabine with cytarabine have been studied in acute leukemia and currently are being evaluated in untreated elderly patients with acute myeloid leukemia. Novel schedules are being explored in lymphoproliferative disorders and solid tumors. Clofarabine is a new nucleoside analog with considerable activity and an acceptable safety profile in acute leukemias.

Adenine Nucleotides↗

PubMed2005

Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP.

Myeloid cell leukemia-1 (MCL-1) acts as a key survival factor for chronic lymphocytic leukemia (CLL) cells. In addition, dissipation of cellular bioenergy may impose a lethal effect on these quiescent cells. Previously, in multiple myeloma cell lines we demonstrated that halogenated adenosine (8-Cl-Ado) was phosphorylated to triphosphate (8-Cl-adenosine triphosphate [ATP]), which preferentially incorporated into mRNA and inhibited RNA synthesis by premature transcription termination. Furthermore, 8-Cl-ATP accumulation was associated with a decline in cellular bioenergy. Based on these actions, we hypothesized that 8-Cl-Ado would be ideal to target CLL lymphocytes. In the present study we demonstrate that leukemic lymphocytes incubated with 8-Cl-Ado display time- and dose-dependent increase in the accumulation of 8-Cl-ATP, with a parallel depletion of the endogenous ATP pool. Inhibition of global RNA synthesis resulted in a significant decline in the expression of transcripts with a short half-life such as MCL1. Consistent to this, protein expression of MCL-1 but not B-cell lymphoma-2 (BCL-2) was decreased. Furthermore, 8-Cl-ATP induced programmed cell death, as suggested by caspases activation, cleavage of caspase 3, and PARP (poly-adenosine diphosphate [ADP]-ribose polymerase), and increased DNA fragmentation. In conclusion, 8-Cl-Ado induces apoptosis in CLL lymphocytes by targeting cellular bioenergy as well as RNA transcription and translation of key survival genes such as MCL1.

Adenosine Triphosphate↗