Invention Reference: 11/MED/424
The ability of cancer cells to acquire resistance to multiple drugs, termed multidrug resistance (MDR), is often mediated by overexpression of ATP-binding cassette (ABC) transporters that remove substrates out of the cell against a concentration gradient. Among 48 human ABC transporters discovered, three, namely P-glycoprotein (P-gp or ABCB1), multidrug resistance-associated protein-1 (MRP-1 or ABCC1), and breast cancer resistance protein (BCRP or ABCG2), are most often associated with MDR. To improve the chemotherapy in multidrug-resistant tumors, numerous ABC transporter inhibitors have been developed and some of them have been tested for their MDR reversal effects in clinical trials. However, attempts to translate the MDR transporter into clinical targets have not been successful and many of these inhibitors also have diverse bioactivities leading to undesirable adverse effects. Therefore, the development of potent MDR inhibitors devoid of other biological activities has become a desirable goal to prove the MDR reversal hypothesis for circumventing drug resistance in anticancer therapy.
This invention provides 11 novel polyoxypregnane (POP) compounds isolated and identified from a Chinese medicinal herb, which distributes mainly in the southwest of China and its dried rhizomes and roots have been used for the treatment of cancer in compound formulation of traditional Chinese medicine for a long history. This invention also provides 4 novel and 10 known POPs, which have also been isolated from this herb, having activities of circumvention of MDR in different cancer cell lines with overexpression of the aforementioned three ABC transporters. Moreover, the active POPs and other inactive POPs coexisting in the herb did not elicit other biological activities, which may lead to their advantages of the absence of other undesirable effects in the body. This invention also provides extraction procedures for the isolation of the said novel and the active POPS, the extracts and pharmaceutical compositions comprising the active POPs, and the methods of testing MDR reversal activity in an in vivo animal model comprising concurrent administration of an amount of at least one active POP, the extract or the pharmaceutical composition with anticancer drug. This invention also provides a method of investigating the relationship between structure and MDR reversal activity of the POPs.
Advantages and improvements over existing technology
As mentioned in the abstract, although numerous ABC transporter inhibitors (which are all synthetic compounds), especially P-gp inhibitors, have been tested in clinical trials, the currently available results are unsuccessful, and many of the inhibitors were found to also have diverse bioactivities, which induce undesirable adverse effects in the patients. Moreover, no clear structure-function relationship has been identified that can explain the definitive requirements for an inhibitor devoid of other biological activities.
While, the advantages of this invention include
1) our POPs are from Chinese medicinal herb, which has been used in cancer patients for a long history, thus they already have the evidence-based outcomes in clinic use, which although may not be scientifically proven yet;
2) this herb is used in numerous compound formulations (複方) and believed to play as a servant (使藥) according to the philosophy (君臣佐使) of traditional Chinese medicine practice. Our studies also revealed the property of the servant function in that all the POPs tested did not have any significant bioactivities in various targets, such as receptors, channels and enzymes tested. Therefore, as ABC transporter inhibitors when concurrently administered with anti-cancer drug(s), the POPs may only circumvent MDR of the drug(s) without inducing other undesirable adverse effects; and
3) our studies have demonstrated that different active POPs exhibited their MDR reversal effects via three differential ABC transporter-mediated mechanisms, thus the developed multiple POP-containing extracts and pharmaceutical compositions have a potential to produce synergistic MDR reversal effects, which will be beneficial in combination therapy with anti-cancer drugs.
