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  • obatoclax An ideal CHK inhibitor would be minimally cytotoxi

    2020-01-14

    An ideal CHK-1 inhibitor would be minimally cytotoxic, while enhancing the anti-tumor effect of a real cytotoxic agent that would be used in combination with the inhibitor. Our CHK-1 inhibitors have shown excellent selectivity over a panel of kinases including those regulating the cell cycle, but these compounds have also shown cytotoxicity to tumor cell lines. Compound had an IC of 0.32nM for CHK-1 with an EC of 80nM (breast cell line MDA-MB-435), while its selectivity ratio for cdk2/cyclin A, cdk4/cyclin D, and cdc2/cyclin B was over 500-, 5000-, and 1500-fold, respectively. More importantly, this class of compounds was synergistic with known cytotoxic agents. When MDA-MB-435 obatoclax were treated with compound and camptothecin (CPT), an inhibitor of topoisomerase 1, compound significantly accelerated cell death ()., This represents a new example of small molecule CHK-1 inhibitors having synergistic activity with traditional cytotoxic agents.
    Introduction Pegylated liposomal doxorubicin (PLD) has been widely used in the treatment of various malignancies, including advanced-stage ovarian carcinoma, metastatic breast cancer, multiple myeloma, and AIDS-related Kaposi’s sarcoma. Encapsulating doxorubicin within liposomes alters its pharmacokinetic and biodistribution profile, resulting in a decrease in doxorubicin-related toxic effects, particularly cardiotoxicity, but frequently results in hand-foot syndrome (HFS) or Palmar–Plantar erythrodysesthesia (PPE) compared with conventional doxorubicin (Rifkin et al., 2006, O’Brien et al., 2004). In severe cases, it can become necessary to reduce the PLD concentration or the duration of the drug therapy, sometimes making it difficult to continue treatment and even resulting in the need for permanent or temporary interruption of treatment (Yokomichi et al., 2013, Bartal et al., 2011). HFS is a highly unpleasant adverse reaction caused by treatment protocols containing PLD, capecitabine, docetaxel, some newly targeted anticancer therapies (sorafenib, axitinib, and sunitinib) or continuously infused 5-fluorouracil. It is characterized as a patchy erythema of the skin of palms and soles, whose primary lesions can sometimes become painful and lead to erosions, desquamation, ulceration, and blister formation (Mangana et al., 2008). HFS is more common among patients who receive a higher dose or more condensed schedule of liposomal doxorubicin treatment. Approximately 50% of patients treated with liposomal doxorubicin at 50mg/m2 every 4 weeks experience some degree of PPE (von Gruenigen et al., 2010, Lawrie et al., 2013). In the phase III trial of PLD 50mg/m2 every 4 weeks in recurrent ovarian cancer, the incidence of grade 3 HFS was 22%. There is currently no validated consensus on how to treat this condition, other than dose reductions. When HFS does develop, reducing the dose intensity (increasing the interval or reducing the dose) is often the most crucial intervention to prevent progression of HFS. Therefore, modified dosing of liposomal doxorubicin using 40mg/m2 every 4 weeks reduces the incidence and severity without compromising clinical efficacy (Al-Batran et al., 2006, Rose, 2005). A prospective clinical trial using 40mg/m2 was conducted in 49 platinum- and paclitaxel-refractory ovarian cancer patients. In this phase II trial, the incidence of PPE of any grade was 18%. No grade 3 or higher HFS was observed (Markman et al., 2000). Liposomal doxorubicin has been detected in eccrine sweat glands, which are more numerous in the palms of the hands and soles of the feet. As the drug accumulates in these tissues, it may cause a local inflammatory tissue reaction (Lorusso et al., 2007). Although data supported the roles of drug excretion in sweat and local pressure as contributors and drug leakage at the capillaries of palms and soles (El-Rayes et al., 2005), the etiology of PPE associated with liposomal doxorubicin was not well elucidated. The efficacy of doxorubicin is based on several mechanisms: intercalation between base pairs of the DNA, generation of free radicals, interactions with cell membranes, and inhibition of topoisomerase II (Wang et al., 2015). Accumulating evidence indicates that uncontrolled apoptosis and stress-induced premature senescence play a key role in the cardiotoxicities of doxorubicin (Piegari et al., 2013, Spallarossa et al., 2010). In addition, Noriyuki Yokomichi demonstrated that PLD penetrates the capillary walls and interacts with Cu (II) ions in the skin to produce reactive oxygen species (ROS), and ROS attacks keratinocytes, which release chemokines and inflammatory cytokines (Yokomichi et al., 2013). Doxorubicin induces apoptosis in cancer cells by causing DNA damage, generation of ROS, cell cycle arrest, and activation of p53 (Mohammad et al., 2015). Based on the role of p53 in the control of apoptosis following DNA damage, exposure to DNA-damaging agents caused an increase of c-Myc, a DNA damage-responsive transcription factor.