The synergistic effect of combination temozolomide and chloroquine treatment is dependent on autophagy formation and p53 status in glioma cells

Re-purposing Chloroquine for Glioblastoma: Potential Merits and Confounding Variables

“…After the initial demonstration that CHQ potentiates therapeutic effects of standard therapy in a double-blinded clinical trial (Phase III) involving a cohort of 30 patients with newly diagnosed GB, (10) further encouraging results have been reported in a case study with 5 patients suffering from recGB treated with CHQ and re-irradiation (18). These observations are coherent with the results from experimental studies indicating that chloroquine can potentiate cytotoxicity of TMZ and ionizing radiation in glioma cells (19–22). …”

“…Activation of p53 signaling upon DNA damage can lead to a transient arrest of the cell cycle, enabling DNA repair, or cell death, if the extent of DNA damage exceeds the repair capacity of the cell. Whereas the ability of CHQ to induce p53-dependent apoptosis has been well-documented (22, 27, 29), the mechanism of p53 activation by CHQ remains elusive. In the canonical DNA damage response (DDR), activation of the ATM/Chk1/p53 signaling is the initial event in a signaling cascade triggered by DNA-double strand breaks (53).…”

Clinical Evidence and Radiobiological Background of Particle Radiation Therapy

“…increases the apoptosis and decreases the proliferation rate of the cells. However, most of the effects of TMZ and CQ in glioma are via differential autophagy-associated mechanisms, and depend on the p53 status [ 44 ].…”

The role of autophagy inhibition in the enhanced cytotoxicity of temozolomide on melanoma cell lines

“…Недавно S. W. Lee и соавт. продемонстрировали, что комбинированное лечение TMZ с CQ не меняло фазу ареста G2-М, но увеличивало популяцию суб-G1 в клетках глиобла-стомы U87 [22]. Активация апоптоза под действием комбинации TMZ с ингибиторами аутофагии.…”

“…При достижении критической концентрации CQ внутри лизосомы он нарушает их ферментативную функцию, действуя как слабое основание, и ингибирует клиренс аутофаголизосомы [21]. В недавних исследованиях показано, что противо-опухолевая комбинация CQ с TMZ приводила к ин-дукции апоптоза в клеточных линиях глиомы с диким типом p53 [22].…”