Antitumor effects of novel compound, guttiferone K, on colon cancer by p21Waf1/Cip1‐mediated G₀/G₁ cell cycle arrest and apoptosis

Abstract

Low selectivity is one of the major problems of currently used anticancer drugs, therefore, there is a high demand for novel, selective antitumor agents. In this study, the anticancer effects and mechanisms of guttiferone K (GUTK), a novel polyprenylated acylphloroglucinol derivative isolated from Garcinia cowa Roxb., were examined for its development as a novel drug targeting colon cancer. GUTK concentration- and time-dependently reduced the viability of human colon cancer HT-29 cells (IC(50) value 5.39 ± 0.22 μM) without affecting the viability of normal human colon epithelial CCD 841 CoN cells and induced G(0) /G(1) cell cycle arrest in HT-29 cells by down-regulating cyclins D1, D3 and cyclin-dependent kinases 4 and 6, while selectively restoring p21Waf1/Cip1 and p27Kip1 to levels comparable to those observed in normal colon cells, without affecting their levels in normal cells. GUTK (10.0 μM) induced cleavage of PARP, caspases-3, -8 and -9 and chromatin condensation to stimulate caspase-3-mediated apoptosis. The addition of a JNK inhibitor, SP600125, partially reversed GUTK-induced caspase-3 activity, indicating the possible involvement of JNK in GUTK-induced apoptosis. Furthermore, GUTK (10 mg/kg, i.p.) significantly decreased the tumor volume in a syngeneic colon tumor model when used alone or in combination with 5-fluorouracil without toxicity to the mice. Immunohistochemical staining of the tumor sections revealed a mechanism involving an increase in cleaved caspase-3 and a decrease in cell proliferation marker Ki-67. Our results support GUTK as a promising novel, potent and selective antitumor drug candidate for colon cancer.

Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro

“…Apoptosis induction by CPT was confirmed using FITC Annexin V apoptosis detection assay and by activation of caspase-3. p21 WAF1/CIP1 and p27 are important inhibitors of cell proliferation by its interactions with complexes of cyclins and cyclin-dependent kinases (CDK) [52] and are also involved in the regulation of apoptosis [53]. Our results show that CPT can also induce p21 and p27 expression in HCT116 and SW480 colorectal cancer cells.…”

Cambogin Induces Caspase-Independent Apoptosis through the ROS/JNK Pathway and Epigenetic Regulation in Breast Cancer Cells

“…It has been reported in previous studies that traditional Chinese herb Garcinia genus possesses therapeutic effects in cancer treatments (8)(9)(10)(11)(12)(13)15). Therefore, we isolated several PPAPs from the Garcinia genus (7) and tested their effects on breast cancer cell proliferation (Fig.…”

“…For decades, PPAPs, the main bioactive components derived from Garcinia genus (Guttiferae family), have been subjected to extensive investigation as likely candidates for cancer treatment (7). For instance, Guttiferone K induced colon cancer G 0 -G 1 cellcycle arrest and apoptosis as a result of p21 Waf1/Cip1 upregulation (8). Oblongifolin C has antitumor effect via autophagic flux inhibition and apoptosis induction in cervical cancer (9,10).…”

ALLN hinders HCT116 tumor growth through Bax-dependent apoptosis

“…In the United States, one in four deaths is due to cancer [1]. Colorectal cancer is the third leading cause of cancer death in each sex and second overall in men and women combined [2]. Although cancer generally reflects growth deregulation at a cellular level, such deregulated cells will normally undergo apoptosis to protect the organism; inactivation of the apoptotic pathway can thus lead to cancer [3], and often, to drug resistance in cancers; such inactivation is sometimes due to mutation of the Bax gene, which is an important regulator of the mitochondrial apoptosis pathway [4][5][6][7].…”