GT198 Is a Target of Oncology Drugs and Anticancer Herbs

Abstract

Tumor angiogenesis is a hallmark of cancer. Therapeutic drug inhibitors targeting angiogenesis are clinically effective. We have previously identified GT198 (gene symbol PSMC3IP, also known as Hop2) as an oncoprotein that induces tumor angiogenesis in human cancers, including oral cancer. In this study, we show that the GT198 protein is a direct drug target of more than a dozen oncology drugs and several clinically successful anticancer herbs. GT198 is a DNA repair protein that binds to DNA. Using an in vitro DNA-binding assay, we tested the approved oncology drug set VII from the National Cancer Institute containing 129 oncology drugs. Identified GT198 inhibitors include but are not limited to mitoxantrone, doxorubicin, paclitaxel, etoposide, dactinomycin, and imatinib. Paclitaxel and etoposide have higher binding affinities, whereas doxorubicin has higher binding efficacy due to competitive inhibition. GT198 shares protein sequence homology with DNA topoisomerases, which are known drug targets, so that GT198 is likely a new drug target previously unrecognized. To seek more powerful GT198 inhibitors, we further tested several anticancer herbal extracts. The positive anticancer herbs with high affinity and high efficacy are all clinically successful ones, including allspice from Jamaica, Gleditsia sinensis or honey locust from China, and BIRM from Ecuador. Partial purification of allspice using an organic chemical approach demonstrated great feasibility of natural product purification, when the activity is monitored by the in vitro DNA-binding assay using GT198 as a target. Together, our study reveals GT198 as a new targeting mechanism for existing oncology drugs. The study also delivers an excellent drug target suitable for compound identification and natural product purification. In particular, this study opens an opportunity to rapidly identify drugs with high efficacy and low toxicity from nature.

Decoding cancer and herbal renaissance

“…In tumors, pericytes carry mutated GT198 ( 27 ), and cause GT198 activation and overexpression ( 7 ). These pericytes evolve into tumor cells resembling the local tissue types such as squamous cells in oral cancer ( 8 ), or glioma cells in brain cancer ( 7 ). The pericyte-derived cells also migrate into tumor-associated lymph nodes suggesting pericyte “cancer stem cells” responsible for tumor metastasis ( 7 ).…”

“…Identified oncology drugs include but are not limited to the well-known mitoxantrone, doxorubicin, paclitaxel, etoposide, and imatinib. The positive anticancer herbs include allspice ( Pimenta Dioica ) from Jamaica, Gleditsia sinensis (ZaoJiaoCi) from China, and BIRM from Ecuador ( 8 ). Unlike oncology drugs restricted to FDA-approved cancer use only, herbal medicines have accumulated a much broader scope of disease treatment, as evidenced in history.…”

“…Not only chemicals could be toxic to our bodies, and the treatment efficacies are not necessarily better. When we compared a collection of most commonly used anticancer chemotherapy drugs to a few anticancer herbs, we already found none of the chemical drugs perfect ( 8 ). They have either poor efficacy like paclitaxel or poor affinity like doxorubicin in inhibiting GT198.…”

“…Recurrent somatic mutations are present in the sporadic breast, ovarian, fallopian tube, prostate, and bladder tumors ( 24 , 27 , 49 , 50 ). More importantly, a number of clinical oncology drugs and clinically effective anticancer herbs directly target to GT198 ( 8 , 9 ). All evidence consistently suggests GT198 as a first-hit oncoprotein.…”

“…Accumulating evidence from us and others has shown that GT198 is mutated in blood vessel pericyte stem cells, which are the primary cancer stem cells causing all human common solid tumors ( 7 ). And importantly, GT198 is a direct target of a panel of successful clinical oncology drugs and anticancer herbs ( 8 , 9 ). Based on the logical theory described in this review, few identified protein factors would have an equal functionality in the human genome, leaving GT198 a unique target of anticancer drugs or herbs.…”