Direct activation of procaspase-3 inhibits human lung adenocarcinoma in a murine model

Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

“…PAC-1 is cytotoxic against a diverse array of cancer cells in culture, including cell lines derived from hematopoietic tumors (lymphoma, ,− leukemia, ,,− and multiple myeloma), carcinomas of diverse origin (breast, ,,− ,− renal, adrenal, , colon, ,,,,, lung, ,− ,− cervical, , gastric, ,,,,, ovarian, liver, ,, prostate, , and gallbladder , ), and other solid tumor histologies (melanoma, ,,, osteosarcoma, neuroblastoma, ,,, and glioblastoma , ). PAC-1 and its derivatives also induce apoptosis in patient-derived samples from colon cancer 8 and chronic lymphocytic leukemia, and have anticancer efficacy in multiple murine tumor models ,,,,− and ...…”

Derivatives of Procaspase-Activating Compound 1 (PAC-1) and their Anticancer Activities

“…[15] PAC-1 and its derivatives induce apoptosis and are cytotoxic in cell culture to a diverse array of cancer cells, including cell lines derived from white blood cell cancers (lymphoma, [15, 42–51] leukemia, [15, 24, 44, 48–50, 52–55] and multiple myeloma [24, 55]), diverse carcinomas (breast, [15, 44, 48, 49, 52–54, 56–59] renal, [15] adrenal, [15, 60–62] colon, [15, 48, 55, 57–59, 63] lung, [15, 48, 49, 52–59, 63–67] cervical, [44, 55] gastric, [48, 49, 55, 57, 58, 63] ovarian, [55] liver, [48, 49, 55] prostate, [48, 49] and gallbladder [48, 49]), and other solid tumor types (melanoma, [15, 44, 48, 49] osteosarcoma, [55] neuroblastoma, [15, 55, 57, 58] and glioblastoma [48, 49, 68]). Patient-derived samples from colon cancer [15], chronic lymphocytic leukemia [23], and multiple myeloma [24] are also sensitive to PAC-1 and derivatives, and a therapeutic effect has been demonstrated in multiple murine tumor models [15, 48, 49, 56, 65, 66, 69] and in pet dogs with cancer. [44] In addition, PAC-1 displays potent synergy with the antitumor agent paclitaxel, [65, 66, 69] as well as 1541B ,[…”

“…Patient-derived samples from colon cancer [15], chronic lymphocytic leukemia [23], and multiple myeloma [24] are also sensitive to PAC-1 and derivatives, and a therapeutic effect has been demonstrated in multiple murine tumor models [15, 48, 49, 56, 65, 66, 69] and in pet dogs with cancer. [44] In addition, PAC-1 displays potent synergy with the antitumor agent paclitaxel, [65, 66, 69] as well as 1541B ,[56] the second reported procaspase-3 activator, [16, 70–72] in various cell culture and in vivo models of cancer, and a derivative of PAC-1 showed synergy with an investigational Smac mimetic in cell culture. [23]…”