Cytotoxic impact of a perillyl alcohol–temozolomide conjugate, NEO212, on cutaneous T-cell lymphoma in vitro

Abstract

Background: Mycosis fungoides (MF) and Sézary syndrome (SS) are subtypes of primary cutaneous lymphomas and represent complex diseases regarding their physiopathology and management. Depending on the stage of the disease, different treatment regimens are applied, but there is no consensus on an optimal approach. Prognosis for patients with early stage MF is favorable, but significantly worsens in advanced disease and in SS, where patients frequently relapse and require multiple therapies. Methods: We investigated the potential anticancer effects of NEO212, a novel compound generated by covalently conjugating perillyl alcohol (a natural monoterpene) to temozolomide (an alkylating agent), on MF and SS cell lines in vitro. HUT-78, HUT-102, and MyLa cells were treated with NEO212 under different conditions, and drug effects on proliferation, viability, and apoptosis were characterized. Results: NEO212 inhibited proliferation, diminished viability, and stimulated apoptosis in all cell lines, although with varying degrees of potency in the different cell lines. It down-regulated c-myc and cyclin D1 proteins, which are required for cell proliferation, but triggered endoplasmic reticulum stress and activation of caspases. Pretreatment of cells with antioxidants ascorbic acid and beta-mercaptoethanol prevented these NEO212-induced effects. Conclusions: NEO212 exerted promising anticancer effects on SS and MF cell lines. The generation of reactive oxygen species (ROS) appears to play a key role in the NEO212-induced cell death process, because the blockage of ROS with antioxidants prevented caspase activation. We propose that NEO212 should be investigated further toward clinical testing in these tumor types.

Pharmacokinetic properties of the temozolomide perillyl alcohol conjugate (NEO212) in mice

“… 18 Beside intracranial tumors, NEO212 was also effective against peripheral cancers, such as subcutaneous melanoma, 20 nasopharyngeal carcinoma, 21 , 22 ovarian carcinoma, 23 lung cancer, 24–26 and cutaneous T-cell lymphoma. 27 In addition, NEO212 exerted activity even against TMZ-resistant cells, irrespective of the underlying resistance mechanism. At the same time, treatment was well tolerated by the tumor-bearing animals and no signs of toxicity could be detected.…”

Dracocephalum heterophyllum (DH) Exhibits Potent Anti-Proliferative Effects on Autoreactive CD4+ T Cells and Ameliorates the Development of Experimental Autoimmune Uveitis

“…*P < 0.05, **P < 0.01, ***P < 0.001. (13,32,33). Regulatory T cells (Tregs), as well as transforming growth factor-b (TGF-b) and IL-10, are known to have important inhibitory functions in CD4 + T-cell proliferation (34)(35)(36).…”

“…As an important component of the immune system, CD4 + T cells play an indispensable role in resisting foreign pathogens and mediate the development of autoimmunity ( 30 , 31 ). Abnormal CD4 + T-cell proliferation has been implicated in the development of various diseases including peripheral T-cell proliferative diseases/lymphomas, inflammatory/infection diseases, graft-versus-host disease and autoimmune diseases ( 13 , 32 , 33 ). Regulatory T cells (Tregs), as well as transforming growth factor-β (TGF-β) and IL-10, are known to have important inhibitory functions in CD4 + T-cell proliferation ( 34 – 36 ).…”

Selected Monocyclic Monoterpenes and Their Derivatives as Effective Anticancer Therapeutic Agents

“…HUT-78 and HUT-102 cells appeared to be more sensitive to NEO212 (IC50 = 3-9 μM) than MyLa cells (IC50 = 85-130 μM) (Table 1). As a result of the binary composition of NEO212 ( 22), this compound is more cytotoxic than its individual components [47]. To overcome POH's low solubility and high volatility issues, Rezende et al studied (S)-(−)-perillyl alcohol 20 complexed with β-cyclodextrin (β-CD) as a possible chemotherapeutic treatment.…”

“…HUT-78 and HUT-102 cells appeared to be more sensitive to NEO212 (IC 50 = 3-9 µM) than MyLa cells (IC 50 = 85-130 µM) (Table 1). As a result of the binary composition of NEO212 (22), this compound is more cytotoxic than its individual components [47].…”